Azadecalin derivatives as inhibitors of human immunodeficiency virus replication

ABSTRACT

Compounds having drug and bio-affecting properties, their pharmaceutical compositions and methods of use are set forth. In particular, azadecaline derivatives that possess unique antiviral activity are provided as HIV maturation inhibitors, as represented by compounds of Formula I: 
                         
These compounds are useful for the treatment of HIV and AIDS.

This application is a § 371 of International Application No.PCT/IB2017/053879, filed 28 Jun. 2017, which claims the benefit of U.S.Provisional Application No. 62/356,829, filed 30 Jun. 2016.

FIELD OF THE INVENTION

The invention relates to compounds, compositions, and methods for thetreatment of human immunodeficiency virus (HIV) infection. Moreparticularly, the invention provides novel azadecalin derivatives asinhibitors of HIV, pharmaceutical compositions containing suchcompounds, and methods for using these compounds in the treatment of HIVinfection. The invention also relates to methods for making thecompounds hereinafter described.

BACKGROUND OF THE INVENTION

Acquired immunodeficiency syndrome (AIDS) is the result of infection byHIV. HIV infection remains a major medical problem, with an estimated45-50 million people infected worldwide at the end of 2011, 3.3 millionof them under the age of 15. In 2011, there were 2.5 million newinfections, and 1.7 million deaths from complications due to HIV/AIDS.

Current therapy for HIV-infected individuals consists of a combinationof approved anti-retroviral agents. Over two dozen drugs are currentlyapproved for HIV infection, either as single agents or as fixed dosecombinations or single tablet regimens, the latter two containing 2-4approved agents. These agents belong to a number of different classes,targeting either a viral enzyme or the function of a viral proteinduring the virus replication cycle. Thus, agents are classified aseither nucleotide reverse transcriptase inhibitors (NRTIs),non-nucleotide reverse transcriptase inhibitors (NNRTIs), proteaseinhibitors (PIs), integrase inhibitors (INIs), or entry inhibitors (one,maraviroc, targets the host CCR5 protein, while the other, enfuvirtide,is a peptide that targets the gp41 region of the viral gp160 protein).In addition, a pharmacokinetic enhancer with no antiviral activity,i.e., cobicistat, available from Gilead Sciences, Inc. under thetradename TYBOST™ (cobicistat) tablets, has recently been approved foruse in combinations with certain antiretroviral agents (ARVs) that maybenefit from boosting.

Despite the armamentarium of agents and drug combinations, there remainsa medical need for new anti-retroviral agents, due in part to the needfor chronic dosing to combat infection. Significant problems related tolong-term toxicities are documented, creating a need to address andprevent these co-morbidities (e.g. CNS, CV/metabolic, renal disease).Also, increasing failure rates on current therapies continue to be aproblem, due either to the presence or emergence of resistant strains orto non-compliance attributed to drug holidays or adverse side effects.For example, despite therapy, it has been estimated that 63% of subjectsreceiving combination therapy remained viremic, as they had viralloads >500 copies/mL (Oette, M, Kaiser, R, Daumer, M, et al. Primary HIVDrug Resistance and Efficacy of First-Line Antiretroviral Therapy Guidedby Resistance Testing. J Acq Imm Def Synd 2006; 41(5):573-581). Amongthese patients, 76% had viruses that were resistant to one or moreclasses of antiretroviral agents. As a result, new drugs are needed thatare easier to take, have high genetic barriers to the development ofresistance and have improved safety over current agents. In this panoplyof choices, novel MOAs that can be used as part of the preferred highlyactive antiretroviral therapy (HAART) regimen can still have a majorrole to play since they should be effective against viruses resistant tocurrent agents.

Certain therapeutic compounds are disclosed in WO 2013/006738, WO2014/110298, and WO 2014/134566.

What is now needed in the art are additional compounds which are noveland useful in the treatment of HIV. Additionally, these compounds maydesirably provide advantages for pharmaceutical uses, for example, withregard to one or more of their mechanisms of action, binding, inhibitionefficacy, target selectivity, solubility, safety profiles, orbioavailability. Also needed are new formulations and methods oftreatment which utilize these compounds.

SUMMARY OF THE INVENTION

The invention encompasses compounds of Formula I, includingpharmaceutically acceptable salts thereof, as well as pharmaceuticalcompositions, and their use in inhibiting HIV and treating thoseinfected with HIV or AIDS.

In one aspect of the invention, there is provided a compound of FormulaI, including pharmaceutically acceptable salts thereof:

wherein X is a phenyl or heteroaryl ring optionally substituted with R₁;R₁ is —H, -halo, -hydroxyl, —C₁₋₆alkyl, —C₁₋₆ alkoxy, —CF₃, and —COOR₂;R₂ is —H, —C₁₋₆ alkyl, -alkylsubstituted C₁₋₆ alkyl or -arylsubstitutedC₁₋₆ alkyl;Y is selected from —COOR₂, —C(O)NR₂SO₂R₃,—C(O)NHSO₂NR₂R₂, —NR₂SO₂R₂,—SO₂NR₂R₂, —C₃₋₆ cycloalkyl-COOR₂, —C₂— alkenyl-COOR₂, —C₂₋₆alkynyl-COOR₂, —C₁₋₆ alkyl-COOR₂, —NHC(O)(CH₂)_(n)—COOR₂, —SO₂NR₂C(O)R₂,-tetrazole, and —CONHOH, wherein n is 1-6;W is selected from —C₁₋₆alkyl, -substituted C₁₋₆alkyl, —C₃₋₁₆carbocycle, -substituted C₃₋₁₆ carbocycle, —C₃₋₁₆ heterocycle,-substituted C₃₋₁₆ hetereocycle, -aryl, -substituted aryl, -heteroaryl,-substituted heteroaryl, —COC₁₋₆alkyl, —COsubstitutedC₁₋₆alkyl,—CO—C₃₋₁₆ carbocycle, —COsubstituted C₃₋₁₆ carbocycle, —COC₃₋₁₆heterocycle, —COsubstituted C₃₋₁₆ hetereocycle, —COaryl, —COsubstitutedaryl, —COheteroaryl, —COsubstituted heteroaryl, —COCOC₁₋₆alkyl,—COCOsubstitutedC₁₋₆alkyl, —COCO—C₃₋₁₆ carbocycle, —COCOsubstitutedC₃₋₁₆ carbocycle, —COCOC₃₋₁₆ heterocycle, —COCOsubstituted C₃₋₁₆hetereocycle, —COCOaryl, —COCOsubstituted aryl, —COCOheteroaryl,—COCOsubstituted heteroaryl,wherein said carbocycles, heterocycles, aryls, and heteroaryls definedherein for W are further selected from monocyclic, bicyclic, andtricyclic systems, wherein the bicyclic and tricyclic systems arefurther selected from fused, non-fused, and spiro systems and whereinsaid substituents on those that are substituted are further selectedfrom —H, -halo, -hydroxyl, —NO₂, —CN, —C₁₋₆ alkyl, —OQ₁, —C₁₋₆ alkoxy,—CF₃, —COOR₂, —NR₃R₄; —COR, —COOR, —SO₂, —SO₂NR₃R₄, and —C₁₋₆ alkylQ₁,—C₁₋₆ alkyl-CO— C₁₋₆ alkyl Q₁, —C₁₋₆ alkyl-NR₃— C₁₋₆ alkyl Q₁, —C₁₋₆alkyl-SO₂C₁₋₆ alkyl Q₁, —C₁₋₆ alkyl-SO₂NR₃— C₁₋₆ alkyl Q₁, —C₁₋₆alkyl-NR₃SO₂— C₁₋₆ alkyl Q₁, —C₁₋₆ alkyl-NR₃CO— C₁₋₆ alkyl Q₁, —C₁₋₆alkyl-CONR₃— C₁₋₆ alkyl Q₁, —C₂₋₆ alkyl-O—C₁₋₆ alkyl Q₁Q₁ is selected from C₃₋₁₆ carbocycle, substituted C₃₋₁₆ carbocycle,C₃₋₁₆ heterocycle, substituted C₃₋₁₆ hetereocycle, aryl, substitutedaryl, heteroaryl, substituted heteroaryl wherein said carbocycles,heterocycles, aryls, and heteroaryls are further selected frommonocyclic, bicyclic, and tricyclic systems, wherein the bicyclic andtricyclic systems are further selected from fused, non-fused, and Spirosystems and wherein said substituents are further selected from —H,-halo, -hydroxyl, —NO₂, —CN, —C₁₋₆ alkyl, —C₁₋₆ alkoxy, —CF₃, —COOR₂,—NR₃R₄; —COR, —COOR, —SO₂, and —SO₂NR₃R₄;alternatively, W is selected from —CO—V, wherein V is selected from—C₁₋₆alkyl, -substituted C₁₋₆alkyl, —C₃₋₁₆ carbocycle, -substitutedC₃₋₁₆ carbocycle, —C₃₋₁₆ heterocycle, -substituted C₃₋₁₆-hetereocycle,-aryl, -substituted aryl, -heteroaryl, -substituted heteroaryl,wherein said carbocycles, heterocycles, aryls, and heteroaryls definedherein for V are further selected from monocyclic, bicyclic, andtricyclic systems, wherein the bicyclic and tricyclic systems arefurther selected from fused, non-fused, and spiro systems and whereinsaid substituents are further selected from —H, -halo, -hydroxyl, —NO₂,—CN, —C₁₋₆ alkyl, —C₁₋₆ alkoxy, —OQ₁, —CF₃, —COOR₂, —NR₃R₄; —COR, —COOR,—SO₂, —SO₂NR₃R₄, and —C₁₋₆ alkylQ₁, —C₁₋₆ alkyl-CO— C₁₋₆ alkyl Q₁, —C₁₋₆alkyl-NR₃— C₁₋₆ alkyl Q₁, —C₁₋₆ alkyl-SO₂C₁₋₆ alkyl Q₁, —C₁₋₆alkyl-SO₂NR₃— C₁₋₆ alkyl Q₁, —C₁₋₆ alkyl-NR₃SO₂— C₁₋₆ alkyl Q₁, —C₁₋₆alkyl-NR₃CO—C₁₋₆ alkyl Q₁, —C₁₋₆ alkyl-CONR₃— C₁₋₆ alkyl Q₁, —C₂₋₆alkyl-O— C₁₋₆ alkyl Q₁;and R₃ and R₄ are independently selected from —H, —C₁₋₆ alkyl, —C₁₋₆substituted alkyl, aryl, heteroaryl, substituted aryl, substitutedheteroaryl, and —COOR₂;alternatively R₃ and R₄ are taken together with the adjacent N to form acycle selected from:

with the proviso that only one of R₃ or R₄ can be —COOR₂.

The invention also relates to pharmaceutical compositions comprising thecompounds of the invention, including pharmaceutically acceptable saltsthereof, and a pharmaceutically acceptable carrier, excipient, and/ordiluent.

In addition, the invention provides one or more methods of treating HIVinfection comprising administering a therapeutically effective amount ofthe compounds of the invention to a patient.

Also provided as part of the invention are one or more methods formaking the compounds of the invention.

The present invention is directed to these, as well as other importantends, hereinafter described.

DETAILED DESCRIPTION OF THE INVENTION

The singular forms “a”, “an”, and “the” include plural reference unlessthe context dictates otherwise.

Unless otherwise expressly set forth elsewhere in the application, thefollowing terms shall have the following meanings:

“Alkenyl” means a straight or branched alkyl group comprised of 2 to 10carbons with at least one double bond and optionally substituted with0-3 halo or alkoxy group.

“Alkenyloxy” means an alkenyl group attached to the parent structure byan oxygen atom.

“Alkoxy” means an alkyl group attached to the parent structure by anoxygen atom.

“Alkoxycarbonyl” means an alkoxy group attached to the parent structureby a carbonyl moiety.

“Alkyl” means a straight or branched saturated hydrocarbon comprised of1 to 10 carbons, and preferably 1 to 6 carbons.

“Alkylthioxy” means an alkyl group attached to the parent structurethrough a sulfur atom.

“Alkynyl” means a straight or branched alkyl group comprised of 2 to 10carbons, preferably 2 to 6 carbons, containing at least one triple bondand optionally substituted with 0-3 halo or alkoxy group.

“Aryl” mean a carbocyclic group comprised of 1-3 rings that are fusedand/or bonded and at least one or a combination of which is aromatic.The non-aromatic carbocyclic portion, where present, will be comprisedof C₃ to C₇ alkyl group. Examples of aromatic group include, but are notlimited to, phenyl, biphenyl, cyclopropylphenyl, indane, naphthalene,and tetrahydronaphthalene. The aryl group can be attached to the parentstructure through any substitutable carbon atom in the group.

“Arylalkyl” is a C₁-C₅ alkyl group attached to 1 to 2 aryl groups andlinked to the parent structure through the alkyl moiety. Examplesinclude, but are not limited to, —(CH₂)_(n)Ph with n is 1-5, —CH(CH₃)Ph,—CH(Ph)₂.

“Aryloxy” is an aryl group attached to the parent structure by oxygen.

“Azaindole” means one of the “CH” moieties in the 6-member ring of anindole is substituted with a nitrogen atom.

“Azaindoline” means one of the aromatic “CH” moieties of an indoline issubstituted with a nitrogen atom.

“Azatetrahydroquinoline” means any aromatic CH moiety oftetrahydroquinoline is substituted with a nitrogen atom.

“Benzyloxy” means a benzyl group is attached to the parent structurethrough an oxygen atom. The phenyl group of the benzyl moiety could beoptionally substituted by 1-3 moieties independently selected fromalkyl, alkoxy, halo, haloalkyl, haloalkoxy and cyano.

“C_(x)-C_(y)” notation indicates a structural element comprised ofcarbons numbering between ‘x’ and ‘y’. For example, “C₅-C₁₀bicycloalkyl” means a bicyclic ring system comprised of 5 to 10 carbons,where the rings are attached in a fused, Spiro or bridged manner; anexample of C₅-C₁₀ bicycloalkyl include, but is not limited to,bicyclo[2.2.2]octane. Similarly, “C₃-C₄ cycloalkyl” is a subset ofmonocyclic ring system comprised of 3 to 4 carbons.

“Cycloalkyl” means a monocyclic ring system comprised of 3 to 7 carbons.

“Cyano” refers to —CN.

“Diazaindole” means any two “CH” moieties in the 6-member ring of anindole are substituted with nitrogen atoms.

“Diazaindoline” means any two aromatic “CH” moieties of an indoline aresubstituted with a nitrogen atom.

“Diazatetrahydroquinoline” means any two aromatic CH moieties oftetrahydroquinoline are substituted with nitrogen atoms.

“Halo” or “halogen” refers to —F, —Cl, —Br, or —I.

“Haloalkyl” means an alkyl group substituted by any combination of oneto six halogen atoms.

“Haloalkoxy” or “Haloalkyloxy” means a haloalkyl group attached to theparent structure through an oxygen atom.

“Hydroxy” refers to —OH.

“Heteroaryl” is a subset of heterocyclic group as defined below and iscomprised of 1-3 rings where at least one or a combination of which isaromatic and that the aromatic group contains at least one atom chosenfrom a group of oxygen, nitrogen or sulfur.

“Heterocyclyl or heterocyclic” means a cyclic group of 1-3 ringscomprised of carbon and at least one other atom selected independentlyfrom oxygen, nitrogen and sulfur. The rings could be bridged, fusedand/or bonded, through a direct or Spiro attachment, with the option tohave one or a combination thereof be aromatic. Examples include, but arenot limited to, azaindole, azaindoline, azetidine, benzimidazole,bezodioxolyl, benzoisothiazole, benzothiazole, benzothiadiazole,benzothiophene, benzoxazole, carbazole, chroman, dihalobezodioxolyl,dihydrobenzofuran, dihydro-benzo[1,4]oxazine,1,3-dihydrobenzo[c]thiophene 2,2-dioxide, 2,3-dihydrobenzo[d]isothiazole1,1-dioxide, 3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazine,2,3-dihydro-1H-pyrrolo[3,4-c]pyridine and its regioisomeric variants,6,7-dihydro-5H-pyrrolo[2,3-b]pyrazine and its regioisomeric variants,furanylphenyl, imidazole, imidazo[1,2-a]pyridine, indazole, indole,indoline, isoquinoline, isoquinolinone, isothiazolidine 1,1-dioxide,morpholine, 2-oxa-5-azabicyclo[2.2.1]heptane, oxadiazole-phenyl,oxazole, phenylaztidine, phenylindazole, phenylpiperidine,phenylpiperizine, phenyloxazole, phenylpyrrolidine, piperidine,pyridine, pyridinylphenyl, pyridinylpyrrolidine, pyrimidine,pyrimidinylphenyl, pyrrazole-phenyl, pyrrolidine, pyrrolidin-2-one,1H-pyrazolo[4,3-c]pyridine and its regioisomeric variants, pyrrole,5H-pyrrolo[2,3-b]pyrazine, 7H-pyrrolo[2,3-d]pyrimidine and itsregioisomeric variants, quinazoline, quinoline, quinoxaline,tetrahydroisoquinoline, 1,2,3,4-tetrahydro-1,8-naphthyridine,tetrahydroquinoline, 4,5,6,7-tetrahydrothieno[3,2-c]pyridine,1,2,5-thiadiazolidine 1,1-dioxide, thiophene, thiophenylphenyl,triazole, or triazolone. Unless otherwise specifically set forth, theheterocyclic group can be attached to the parent structure through anysuitable atom in the group that results in a stable compound.

It is understood that a subset of the noted heterocyclic examplesencompass regioisomers. For instance, “azaindole” refers to any of thefollowing regioisomers: 1H-pyrrolo[2,3-b]pyridine,1H-pyrrolo[2,3-c]pyridine, 1H-pyrrolo[3,2-c]pyridine, and1H-pyrrolo[3,2-b]pyridine. In addition the “regioisomer variants”notation as in, for example, “5H-pyrrolo[2,3-b]pyrazine and itsregioisomeric variants” would also encompass7H-pyrrolo[2,3-d]pyrimidine, 7H-pyrrolo[2,3-c]pyridazine,1H-pyrrolo[2,3-d]pyridazine, 5H-pyrrolo[3,2-c]pyridazine, and5H-pyrrolo[3,2-d]pyrimidine. Similarly,6,7-dihydro-5H-pyrrolo[2,3-b]pyrazine and its regioisomeric variantswould encompass 6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidine and6,7-dihydro-5H-pyrrolo[2,3-c]pyridazine. It is also understood that thelack of “regioisomeric variants” notation does not in any way restrictthe claim scope to the noted example only.

“Heterocyclylalkyl” is a heterocyclyl moiety attached to the parentstructure through C₁-C₅ alkyl group. Examples include, but are notlimited to, —(CH₂)_(n)—R^(Z) or —CH(CH₃)—(R^(Z)) where n is 1-5 and thatR^(Z) is chosen from benzimidazole, imidazole, indazole, isooxazole,phenyl-pyrazole, pyridine, quinoline, thiazole, triazole, triazolone,oxadiazole.

The compounds of the present invention can be referred to as azadecalinderivatives, as they generally contain a fused 10-membered ringstructure containing a nitrogen atom. The structures for decalin and anazadecalin are shown for reference immediately below.

With respect to the azadecalin derviatives of the present invention, itshould be noted that for Formula I, the structures are represented withdotted lines for some of the bonds. This convention with the dottedlines is to indicate that the bond at the indicated site canindependently be selected from a single bond or a double bond. See,below the representation for Formula I where these bonds are shown withthe dotted line notation.

“Tetrahydroquinoline” means 1,2,3,4-tetrahydroquinoline.

Substituents which are illustrated by chemical drawing to bond atvariable positions on a multiple ring system (for example a bicyclicring system) are intended to bond to the ring where they are drawn toappend. Parenthetic and multiparenthetic terms are intended to clarifybonding relationships to those skilled in the art. For example, a termsuch as ((R)alkyl) means an alkyl substituent further substituted withthe substituent R.

Those terms not specifically set forth herein shall have the meaningwhich is commonly understood and accepted in the art.

The invention includes all pharmaceutically acceptable salt forms of thecompounds. Pharmaceutically acceptable salts are those in which thecounter ions do not contribute significantly to the physiologicalactivity or toxicity of the compounds and as such function aspharmacological equivalents. These salts can be made according to commonorganic techniques employing commercially available reagents. Someanionic salt forms include acetate, acistrate, besylate, bromide,chloride, citrate, fumarate, glucouronate, hydrobromide, hydrochloride,hydroiodide, iodide, lactate, maleate, mesylate, nitrate, pamoate,phosphate, succinate, sulfate, tartrate, tosylate, and xinofoate. Somecationic salt forms include ammonium, aluminum, benzathine, bismuth,calcium, choline, diethylamine, diethanolamine, lithium, magnesium,meglumine, 4-phenylcyclohexylamine, piperazine, potassium, sodium,tromethamine, and zinc.

Some of the compounds of the invention exist in stereoisomeric forms.The invention includes all stereoisomeric forms of the compoundsincluding enantiomers and diastereromers. Methods of making andseparating stereoisomers are known in the art. The invention includesall tautomeric forms of the compounds. The invention includesatropisomers and rotational isomers.

The invention is intended to include all isotopes of atoms occurring inthe present compounds. Isotopes include those atoms having the sameatomic number but different mass numbers. By way of general example andwithout limitation, isotopes of hydrogen include deuterium and tritium.Isotopes of carbon include ¹³C and ¹⁴C. Isotopically-labeled compoundsof the invention can generally be prepared by conventional techniquesknown to those skilled in the art or by processes analogous to thosedescribed herein, using an appropriate isotopically-labeled reagent inplace of the non-labeled reagent otherwise employed. Such compounds mayhave a variety of potential uses, for example as standards and reagentsin determining biological activity. In the case of stable isotopes, suchcompounds may have the potential to favorably modify biological,pharmacological, or pharmacokinetic properties.

For the sake of efficiency some ring structures are shown with avariable number of members in the ring. For example, the following ringsubstituent

having the parenthetical “( )_(1,2)” is intended to encompass both asingle carbon group, —(CH₂)—, and a two carbon group, —(CH₂CH₂)—. Theintended ring structures could individually be depicted as:

The compounds of the invention also include “prodrugs”. The term“prodrug” as used herein encompasses both the term “prodrug esters” andthe term “prodrug ethers”.

In an aspect of the invention, there is provided a compound of FormulaI, including pharmaceutically acceptable salts thereof:

wherein X is a phenyl or heteroaryl ring optionally substituted with R₁;R₁ is —H, -halo, -hydroxyl, —C₁₋₆ alkyl, —C₁₋₆ alkoxy, —CF₃, and —COOR₂;R₂ is —H, —C₁₋₆ alkyl, -alkylsubstituted C₁₋₆ alkyl or -arylsubstitutedC₁₋₆ alkyl;Y is selected from —COOR₂, —C(O)NR₂SO₂R₃,—C(O)NHSO₂NR₂R₂, —NR₂SO₂R₂,—SO₂NR₂R₂, —C₃₋₆ cycloalkyl-COOR₂, —C₂₋₆ alkenyl-COOR₂, —C₂₋₆alkynyl-COOR₂, —C₁₋₆ alkyl-COOR₂, —NHC(O)(CH₂)_(n)—COOR₂, —SO₂NR₂C(O)R₂,-tetrazole, and —CONHOH, wherein n is 1-6;

W is selected from —C₁₋₆alkyl, -substituted C₁₋₆alkyl, —C₃₋₁₆carbocycle, -substituted C₃₋₁₆ carbocycle, —C₃₋₁₆ heterocycle,-substituted C₃₋₁₆ hetereocycle, -aryl, -substituted aryl, -heteroaryl,-substituted heteroaryl, —COC₁₋₆alkyl, —COsubstitutedC₁₋₆alkyl,—CO—C₃₋₁₆ carbocycle, —COsubstituted C₃₋₁₆ carbocycle, —COC₃₋₁₆heterocycle, —COsubstituted C₃₋₁₆ hetereocycle, —COaryl, —COsubstitutedaryl, —COheteroaryl, —COsubstituted heteroaryl, —COCOC₁₋₆alkyl,—COCOsubstitutedC₁₋₆alkyl, —COCO—C₃₋₁₆ carbocycle, —COCOsubstitutedC₃₋₁₆ carbocycle, —COCOC₃₋₁₆ heterocycle, —COCOsubstituted C₃₋₁₆hetereocycle, —COCOaryl, —COCOsubstituted aryl, —COCOheteroaryl,—COCOsubstituted heteroaryl,

wherein said carbocycles, heterocycles, aryls, and heteroaryls definedherein for W are further selected from monocyclic, bicyclic, andtricyclic systems, wherein the bicyclic and tricyclic systems arefurther selected from fused, non-fused, and spiro systems and whereinsaid substituents on those that are substituted are further selectedfrom —H, -halo, -hydroxyl, —NO₂, —CN, —C₁₋₆ alkyl, —OQ₁, —C₁₋₆ alkoxy,—CF₃, —COOR₂, —NR₃R₄; —COR, —COOR, —SO₂, —SO₂NR₃R₄, and —C₁₋₆ alkylQ₁,—C₁₋₆ alkyl-CO— C₁₋₆ alkyl Q₁, —C₁₋₆ alkyl-NR₃— C₁₋₆ alkyl Q₁, —C₁₋₆alkyl-SO₂C₁₋₆ alkyl Q₁, —C₁₋₆ alkyl-SO₂NR₃— C₁₋₆ alkyl Q₁, —C₁₋₆alkyl-NR₃SO₂— C₁₋₆ alkyl Q₁, —C₁₋₆ alkyl-NR₃CO— C₁₋₆ alkyl Q₁, —C₁₋₆alkyl-CONR₃— C₁₋₆ alkyl Q₁, —C₂₋₆ alkyl-O—C₁₋₆ alkyl Q₁Q₁ is selected from C₃₋₁₆ carbocycle, substituted C₃₋₁₆ carbocycle,C₃₋₁₆ heterocycle, substituted C₃₋₁₆ hetereocycle, aryl, substitutedaryl, heteroaryl, substituted heteroaryl wherein said carbocycles,heterocycles, aryls, and heteroaryls are further selected frommonocyclic, bicyclic, and tricyclic systems, wherein the bicyclic andtricyclic systems are further selected from fused, non-fused, and spirosystems and wherein said substituents are further selected from —H,-halo, -hydroxyl, —NO₂, —CN, —C₁₋₆ alkyl, —C₁₋₆ alkoxy, —CF₃, —COOR₂,—NR₃R₄; —COR, —COOR, —SO₂, and —SO₂NR₃R₄;alternatively, W is selected from —CO—V, wherein V is selected from—C₁₋₆alkyl, -substituted C₁₋₆alkyl, —C₃₋₁₆ carbocycle, -substitutedC₃₋₁₆ carbocycle, —C₃₋₁₆ heterocycle, -substituted C₃₋₁₆-hetereocycle,-aryl, -substituted aryl, -heteroaryl, -substituted heteroaryl,wherein said carbocycles, heterocycles, aryls, and heteroaryls definedherein for V are further selected from monocyclic, bicyclic, andtricyclic systems, wherein the bicyclic and tricyclic systems arefurther selected from fused, non-fused, and spiro systems and whereinsaid substituents are further selected from —H, -halo, -hydroxyl, —NO₂,—CN, —C₁₋₆ alkyl, —C₁₋₆ alkoxy, —OQ₁, —CF₃, —COOR₂, —NR₃R₄; —COR, —COOR,—SO₂, —SO₂NR₃R₄, and —C₁₋₆ alkylQ₁, —C₁₋₆ alkyl-CO— C₁₋₆ alkyl Q₁, —C₁₋₆alkyl-NR₃— C₁₋₆ alkyl Q₁, —C₁₋₆ alkyl-SO₂C₁₋₆ alkyl Q₁, —C₁₋₆alkyl-SO₂NR₃— C₁₋₆ alkyl Q₁, —C₁₋₆ alkyl-NR₃SO₂— C₁₋₆ alkyl Q₁,alkyl-NR₃CO— C₁₋₆ alkyl Q₁, —C₁₋₆ alkyl-CONR₃— C₁₋₆ alkyl Q₁, —C₂₋₆alkyl-O— C₁₋₆ alkyl Q₁;and R₃ and R₄ are independently selected from —H, —C₁₋₆ alkyl, —C₁₋₆substituted alkyl, aryl, heteroaryl, substituted aryl, substitutedheteroaryl, and —COOR₂;alternatively R₃ and R₄ are taken together with the adjacent N to form acycle selected from:

with the proviso that only one of R₃ or R₄ can be —COOR₂.

In an aspect of the invention, there is provided a compound of FormulaI, wherein X is phenyl.

In an aspect of the invention, there is provided a compound of FormulaI, wherein Y is —COOR₂.

In an aspect of the invention, there is provided a compound of FormulaI, wherein Y is —COOH.

In an aspect of the invention, there is provided a compound of FormulaI, wherein R₁ is H.

In an aspect of the invention, there is provided a compound of FormulaI, wherein W is —COV.

In an aspect of the invention, there is provided a compound of

including pharmaceutically acceptable salts thereof:wherein X is a phenyl or heteroaryl ring optionally substituted with R₁;R₁ is —H, -halo, -hydroxyl, —C₁₋₆alkyl, —C₁₋₆ alkoxy, —CF₃, and —COOR₂;R₂ is —H, —C₁₋₆ alkyl, -alkylsubstituted C₁₋₆ alkyl or -arylsubstitutedC₁₋₆alkyl;Y is selected from —COOR₂, —C(O)NR₂SO₂R₃,—C(O)NHSO₂NR₂R₂, —NR₂SO₂R₂,—SO₂NR₂R₂, —C₃₋₆ cycloalkyl-COOR₂, —C₂₋₆ alkenyl-COOR₂, —C₂₋₆alkynyl-COOR₂, —C₁₋₆ alkyl-COOR₂, —NHC(O)(CH₂)_(n)—COOR₂, —SO₂NR₂C(O)R₂,-tetrazole, and —CONHOH, wherein n is 1-6;W is selected from —C₁₋₆alkyl, -substituted C₁₋₆alkyl, —C₃₋₁₆carbocycle, -substituted C₃₋₁₆ carbocycle, —C₃₋₁₆ heterocycle,-substituted C₃₋₁₆ hetereocycle, -aryl, -substituted aryl, -heteroaryl,-substituted heteroaryl, —COC₁₋₆alkyl, —COsubstitutedC₁₋₆alkyl,—CO—C₃₋₁₆ carbocycle, —COsubstituted C₃₋₁₆ carbocycle, —COC₃₋₁₆heterocycle, —COsubstituted C₃₋₁₆ hetereocycle, —COaryl, —COsubstitutedaryl, —COheteroaryl, —COsubstituted heteroaryl, —COCOC₁₋₆alkyl,—COCOsubstitutedC₁₋₆alkyl, —COCO—C₃₋₁₆ carbocycle, —COCOsubstitutedC₃₋₁₆ carbocycle, —COCOC₃₋₁₆ heterocycle, —COCOsubstituted C₃₋₁₆hetereocycle, —COCOaryl, —COCOsubstituted aryl, —COCOheteroaryl,—COCOsubstituted heteroaryl,wherein said carbocycles, heterocycles, aryls, and heteroaryls definedherein for W are further selected from monocyclic, bicyclic, andtricyclic systems, wherein the bicyclic and tricyclic systems arefurther selected from fused, non-fused, and spiro systems and whereinsaid substituents on those that are substituted are further selectedfrom —H, -halo, -hydroxyl, —NO₂, —CN, —C₁₋₆alkyl, —OQ₁, —C₁₋₆ alkoxy,—CF₃, —COOR₂, —NR₃R₄; —COR, —COOR, —SO₂, —SO₂NR₃R₄, and —C₁₋₆alkylQ₁,—C₁₋₆ alkyl-CO— C₁₋₆ alkyl Q₁, —C₁₋₆alkyl-NR₃— C₁₋₆ alkyl Q₁, —C₁₋₆alkyl-SO₂C₁₋₆ alkyl Q₁, —C₁₋₆ alkyl-SO₂NR₃— C₁₋₆ alkyl Q₁, —C₁₋₆alkyl-NR₃SO₂— C₁₋₆ alkyl Q₁, —C₁₋₆ alkyl-NR₃CO—C₁₋₆ alkyl Q₁, —C₁₋₆alkyl-CONR₃— C₁₋₆ alkyl Q₁, —C₂₋₆ alkyl-O—C₁₋₆ alkyl Q₁Q₁ is selected from C₃₋₁₆ carbocycle, substituted C₃₋₁₆ carbocycle,C₃₋₁₆ heterocycle, substituted C₃₋₁₆ hetereocycle, aryl, substitutedaryl, heteroaryl, substituted heteroaryl wherein said carbocycles,heterocycles, aryls, and heteroaryls are further selected frommonocyclic, bicyclic, and tricyclic systems, wherein the bicyclic andtricyclic systems are further selected from fused, non-fused, and spirosystems and wherein said substituents are further selected from —H,-halo, -hydroxyl, —NO₂, —CN, —C₁₋₆alkyl, —C₁₋₆ alkoxy, —CF₃, —COOR₂,—NR₃R₄; —COR, —COOR, —SO₂, and —SO₂NR₃R₄;alternatively, W is selected from —CO—V, wherein V is selected from—C₁₋₆alkyl, -substituted C₁₋₆alkyl, —C₃₋₁₆ carbocycle, -substitutedC₃₋₁₆ carbocycle, —C₃₋₁₆ heterocycle, -substituted C₃₋₁₆-hetereocycle,-aryl, -substituted aryl, -heteroaryl, -substituted heteroaryl,wherein said carbocycles, heterocycles, aryls, and heteroaryls definedherein for V are further selected from monocyclic, bicyclic, andtricyclic systems, wherein the bicyclic and tricyclic systems arefurther selected from fused, non-fused, and spiro systems and whereinsaid substituents are further selected from —H, -halo, -hydroxyl, —NO₂,—CN, —C₁₋₆ alkyl, —C₁₋₆ alkoxy, —OQ₁, —CF₃, —COOR₂, —NR₃R₄; —COR, —COOR,—SO₂, —SO₂NR₃R₄, and —C₁₋₆ alkylQ₁, —C₁₋₆ alkyl-CO— C₁₋₆ alkyl Q₁, —C₁₋₆alkyl-NR₃— C₁₋₆ alkyl Q₁, —C₁₋₆ alkyl-SO₂C₁₋₆ alkyl Q₁, —C₁₋₆alkyl-SO₂NR₃— C₁₋₆ alkyl Q₁, —C₁₋₆ alkyl-NR₃SO₂— C₁₋₆ alkyl Q₁, —C₁₋₆alkyl-NR₃CO— C₁₋₆ alkyl Q₁, —C₁₋₆ alkyl-CONR₃— C₁₋₆ alkyl Q₁, —C₂₋₆alkyl-O— C₁₋₆ alkyl Q₁;and R₃ and R₄ are independently selected from —H, —C₁₋₆ alkyl, —C₁₋₆substituted alkyl, aryl, heteroaryl, substituted aryl, substitutedheteroaryl, and —COOR₂;alternatively R₃ and R₄ are taken together with the adjacent N to form acycle selected from:

with the proviso that only one of R₃ or R₄ can be —COOR₂.

In an aspect of the invention, there is provided a compound of FormulaII, including pharmaceutically acceptable salts thereof:

wherein X is a phenyl or heteroaryl ring optionally substituted with R₁;R₁ is —H, -halo, -hydroxyl, —C₁₋₆ alkyl, —C₁₋₆ alkoxy, —CF₃, and —COOR₂;R₂ is —H, —C₁₋₆ alkyl, -alkylsubstituted C₁₋₆ alkyl or -arylsubstitutedC₁₋₆ alkyl;Y is selected from —COOR₂, —C(O)NR₂SO₂R₃,—C(O)NHSO₂NR₂R₂, —NR₂SO₂R₂,—SO₂NR₂R₂, —C₃₋₆ cycloalkyl-COOR₂, —C₂₋₆ alkenyl-COOR₂, —C₂₋₆alkynyl-COOR₂, —C₁₋₆ alkyl-COOR₂, —NHC(O)(CH₂)_(n)—COOR₂, —SO₂NR₂C(O)R₂,-tetrazole, and —CONHOH, wherein n is 1-6;W is selected from —C₁₋₆alkyl, -substituted C₁₋₆alkyl, —C₃₋₁₆carbocycle, -substituted C₃₋₁₆ carbocycle, —C₃₋₁₆ heterocycle,-substituted C₃₋₁₆ hetereocycle, -aryl, -substituted aryl, -heteroaryl,-substituted heteroaryl, —COC₁₋₆alkyl, —COsubstitutedC₁₋₆alkyl,—CO—C₃₋₁₆ carbocycle, —COsubstituted C₃₋₁₆ carbocycle, —COC₃₋₁₆heterocycle, —COsubstituted C₃₋₁₆ hetereocycle, —COaryl, —COsubstitutedaryl, —COheteroaryl, —COsubstituted heteroaryl, —COCOC₁₋₆alkyl,—COCOsubstitutedC₁₋₆alkyl, —COCO—C₃₋₁₆ carbocycle, —COCOsubstitutedC₃₋₁₆ carbocycle, —COCOC₃₋₁₆ heterocycle, —COCOsubstituted C₃₋₁₆hetereocycle, —COCOaryl, —COCOsubstituted aryl, —COCOheteroaryl,—COCOsubstituted heteroaryl,wherein said carbocycles, heterocycles, aryls, and heteroaryls definedherein for W are further selected from monocyclic, bicyclic, andtricyclic systems, wherein the bicyclic and tricyclic systems arefurther selected from fused, non-fused, and spiro systems and whereinsaid substituents on those that are substituted are further selectedfrom —H, -halo, -hydroxyl, —NO₂, —CN, —C₁₋₆ alkyl, —OQ₁, —C₁₋₆ alkoxy,—CF₃, —COOR₂, —NR₃R₄; —COR, —COOR, —SO₂, —SO₂NR₃R₄, and —C₁₋₆ alkylQ₁,—C₁₋₆ alkyl-CO— C₁₋₆ alkyl Q₁, —C₁₋₆ alkyl-NR₃—C₁₋₆ alkyl Q₁, —C₁₋₆alkyl-SO₂C₁₋₆ alkyl Q₁, —C₁₋₆ alkyl-SO₂NR₃— C₁₋₆ alkyl Q₁, —C₁₋₆alkyl-NR₃SO₂— C₁₋₆ alkyl Q₁, —C₁₋₆ alkyl-NR₃CO— C₁₋₆ alkyl Q₁, —C₁₋₆alkyl-CONR₃— C₁₋₆ alkyl Q₁, —C₂₋₆ alkyl-O—C₁₋₆ alkyl Q₁Q₁ is selected from C₃₋₁₆ carbocycle, substituted C₃₋₁₆ carbocycle,C₃₋₁₆ heterocycle, substituted C₃₋₁₆ hetereocycle, aryl, substitutedaryl, heteroaryl, substituted heteroaryl wherein said carbocycles,heterocycles, aryls, and heteroaryls are further selected frommonocyclic, bicyclic, and tricyclic systems, wherein the bicyclic andtricyclic systems are further selected from fused, non-fused, and spirosystems and wherein said substituents are further selected from —H,-halo, -hydroxyl, —NO₂, —CN, —C₁₋₆ alkyl, —C₁₋₆ alkoxy, —CF₃, —COOR₂,—NR₃R₄; —COR, —COOR, —SO₂, and —SO₂NR₃R₄;alternatively, W is selected from —CO—V, wherein V is selected from—C₁₋₆alkyl, -substituted C₁₋₆alkyl, —C₃₋₁₆ carbocycle, -substitutedC₃₋₁₆ carbocycle, —C₃₋₁₆ heterocycle, -substituted C₃₋₁₆-hetereocycle,-aryl, -substituted aryl, -heteroaryl, -substituted heteroaryl,wherein said carbocycles, heterocycles, aryls, and heteroaryls definedherein for V are further selected from monocyclic, bicyclic, andtricyclic systems, wherein the bicyclic and tricyclic systems arefurther selected from fused, non-fused, and spiro systems and whereinsaid substituents are further selected from —H, -halo, -hydroxyl, —NO₂,—CN, —C₁₋₆ alkyl, —C₁₋₆ alkoxy, —OQ₁, —CF₃, —COOR₂, —NR₃R₄; —COR, —COOR,—SO₂, —SO₂NR₃R₄, and —C₁₋₆ alkylQ₁, —C₁₋₆ alkyl-CO— C₁₋₆ alkyl Q₁, —C₁₋₆alkyl-NR₃— C₁₋₆ alkyl Q₁, —C₁₋₆ alkyl-SO₂C₁₋₆ alkyl Q₁, —C₁₋₆alkyl-SO₂NR₃— C₁₋₆ alkyl Q₁, —C₁₋₆ alkyl-NR₃SO₂— C₁₋₆ alkyl Q₁, —C₁₋₆alkyl-NR₃CO— C₁₋₆ alkyl Q₁, —C₁₋₆ alkyl-CONR₃— C₁₋₆ alkyl Q₁, —C₂₋₆alkyl-O— C₁₋₆ alkyl Q₁;and R₃ and R₄ are independently selected from —H, —C₁₋₆ alkyl, —C₁₋₆substituted alkyl, aryl, heteroaryl, substituted aryl, substitutedheteroaryl, and —COOR₂;alternatively R₃ and R₄ are taken together with the adjacent N to form acycle selected from:

with the proviso that only one of R₃ or R₄ can be —COOR₂.

In an aspect of the invention, there is provided a compound of

including pharmaceutically acceptable salts thereof:wherein X is a phenyl or heteroaryl ring optionally substituted with R₁;R₁ is —H, -halo, -hydroxyl, —C₁₋₆ alkyl, —C₁₋₆ alkoxy, —CF₃, and —COOR₂;R₂ is —H, —C₁₋₆ alkyl, -alkylsubstituted C₁₋₆ alkyl or -arylsubstitutedC₁₋₆ alkyl;Y is selected from —COOR₂, —C(O)NR₂SO₂R₃,—C(O)NHSO₂NR₂R₂, —NR₂SO₂R₂,—SO₂NR₂R₂, —C₃₋₆ cycloalkyl-COOR₂, —C₂₋₆ alkenyl-COOR₂, —C₂₋₆alkynyl-COOR₂, —C₁₋₆ alkyl-COOR₂, —NHC(O)(CH₂)_(n)—COOR₂, —SO₂NR₂C(O)R₂,-tetrazole, and —CONHOH, wherein n is 1-6;W is selected from —C₁₋₆alkyl, -substituted C₁₋₆alkyl, —C₃₋₁₆carbocycle, -substituted C₃₋₁₆ carbocycle, —C₃₋₁₆ heterocycle,-substituted C₃₋₁₆ hetereocycle, -aryl, -substituted aryl, -heteroaryl,-substituted heteroaryl, —COC₁₋₆alkyl, —COsubstitutedC₁₋₆alkyl,—CO—C₃₋₁₆ carbocycle, —COsubstituted C₃₋₁₆ carbocycle, —COC₃₋₁₆heterocycle, —COsubstituted C₃₋₁₆ hetereocycle, —COaryl, —COsubstitutedaryl, —COheteroaryl, —COsubstituted heteroaryl, —COCOC₁₋₆alkyl,—COCOsubstitutedC₁₋₆alkyl, —COCO—C₃₋₁₆ carbocycle, —COCOsubstitutedC₃₋₁₆ carbocycle, —COCOC₃₋₁₆ heterocycle, —COCOsubstituted C₃₋₁₆hetereocycle, —COCOaryl, —COCOsubstituted aryl, —COCOheteroaryl,—COCOsubstituted heteroaryl,wherein said carbocycles, heterocycles, aryls, and heteroaryls definedherein for W are further selected from monocyclic, bicyclic, andtricyclic systems, wherein the bicyclic and tricyclic systems arefurther selected from fused, non-fused, and spiro systems and whereinsaid substituents on those that are substituted are further selectedfrom —H, -halo, -hydroxyl, —NO₂, —CN, —C₁₋₆ alkyl, —OQ₁, —C₁₋₆ alkoxy,—CF₃, —COOR₂, —NR₃R₄; —COR, —COOR, —SO₂, —SO₂NR₃R₄, and —C₁₋₆ alkylQ₁,—C₁₋₆ alkyl-CO— C₁₋₆ alkyl Q₁, —C₁₋₆ alkyl-NR₃— C₁₋₆ alkyl Q₁, —C₁₋₆alkyl-SO₂C₁₋₆ alkyl Q₁, —C₁₋₆ alkyl-SO₂NR₃— C₁₋₆ alkyl Q₁, —C₁₋₆alkyl-NR₃SO₂— C₁₋₆ alkyl Q₁, —C₁₋₆ alkyl-NR₃CO—C₁₋₆ alkyl Q₁, —C₁₋₆alkyl-CONR₃—C₁₋₆ alkyl Q₁, —C₂₋₆ alkyl-O—C₁₋₆ alkyl Q₁Q₁ is selected from C₃₋₁₆ carbocycle, substituted C₃₋₁₆ carbocycle,C₃₋₁₆ heterocycle, substituted C₃₋₁₆ hetereocycle, aryl, substitutedaryl, heteroaryl, substituted heteroaryl wherein said carbocycles,heterocycles, aryls, and heteroaryls are further selected frommonocyclic, bicyclic, and tricyclic systems, wherein the bicyclic andtricyclic systems are further selected from fused, non-fused, and spirosystems and wherein said substituents are further selected from —H,-halo, -hydroxyl, —NO₂, —CN, —C₁₋₆ alkyl, —C₁₋₆ alkoxy, —CF₃, —COOR₂,—NR₃R₄; —COR, —COOR, —SO₂, and —SO₂NR₃R₄;alternatively, W is selected from —CO—V, wherein V is selected from—C₁₋₆alkyl, -substituted C₁₋₆alkyl, —C₃₋₁₆ carbocycle, -substitutedC₃₋₁₆ carbocycle, —C₃₋₁₆ heterocycle, -substituted C₃₋₁₆-hetereocycle,-aryl, -substituted aryl, -heteroaryl, -substituted heteroaryl,wherein said carbocycles, heterocycles, aryls, and heteroaryls definedherein for V are further selected from monocyclic, bicyclic, andtricyclic systems, wherein the bicyclic and tricyclic systems arefurther selected from fused, non-fused, and Spiro systems and whereinsaid substituents are further selected from —H, -halo, -hydroxyl, —NO₂,—CN, —C₁₋₆ alkyl, —C₁₋₆ alkoxy, —OQ₁, —CF₃, —COOR₂, —NR₃R₄; —COR, —COOR,—SO₂, —SO₂NR₃R₄, and —C₁₋₆ alkylQ₁, —C₁₋₆ alkyl-CO— C₁₋₆ alkyl Q₁, —C₁₋₆alkyl-NR₃— C₁₋₆ alkyl Q₁, —C₁₋₆ alkyl-SO₂C₁₋₆ alkyl Q₁, —C₁₋₆alkyl-SO₂NR₃— C₁₋₆ alkyl Q₁, —C₁₋₆ alkyl-NR₃SO₂— C₁₋₆ alkyl Q₁, —C₁₋₆alkyl-NR₃CO—C₁₋₆ alkyl Q₁, —C₁₋₆ alkyl-CONR₃— C₁₋₆ alkyl Q₁, —C₂₋₆alkyl-O— C₁₋₆ alkyl Q₁;and R₃ and R₄ are independently selected from —H, —C₁₋₆ alkyl, —C₁₋₆substituted alkyl, aryl, heteroaryl, substituted aryl, substitutedheteroaryl, and —COOR₂;alternatively R₃ and R₄ are taken together with the adjacent N to form acycle selected from:

with the proviso that only one of R₃ or R₄ can be —COOR₂.

In an aspect of the invention, there is provided a compound of FormulaX, including pharmaceutically acceptable salts thereof:

wherein V is selected from —C₁₋₆alkyl, -substituted C₁₋₆alkyl, —C₃₋₁₆carbocycle, -substituted C₃₋₁₆ carbocycle, —C₃₋₁₆ heterocycle,-substituted C₃₋₁₆-hetereocycle, -aryl, -substituted aryl, -heteroaryl,-substituted heteroaryl,wherein said carbocycles, heterocycles, aryls, and heteroaryls definedherein for V are further selected from monocyclic, bicyclic, andtricyclic systems, wherein the bicyclic and tricyclic systems arefurther selected from fused, non-fused, and spiro systems and whereinsaid substituents are further selected from —H, -halo, -hydroxyl, —NO₂,—CN, —C₁₋₆ alkyl, —C₁₋₆ alkoxy, —OQ₁, —CF₃, —COOR₂, —NR₃R₄; —COR, —COOR,—SO₂, —SO₂NR₃R₄, and —C₁₋₅ alkylQ₁, —C₁₋₆ alkyl-CO— C₁₋₆ alkyl Q₁, —C₁₋₆alkyl-NR₃— C₁₋₆ alkyl Q₁, —C₁₋₆ alkyl-SO₂C₁₋₆ alkyl Q₁, —C₁₋₆alkyl-SO₂NR₃— C₁₋₆ alkyl Q₁, —C₁₋₆ alkyl-NR₃SO₂— C₁₋₆ alkyl Q₁, —C₁₋₆alkyl-NR₃CO— C₁₋₆ alkyl Q₁, —C₁₋₆ alkyl-CONR₃— C₁₋₆ alkyl Q₁, —C₂₋₆alkyl-O— C₁₋₆ alkyl Q₁;Q₁ is selected from C₃₋₁₆ carbocycle, substituted C₃₋₁₆ carbocycle,C₃₋₁₆ heterocycle, substituted C₃₋₁₆ hetereocycle, aryl, substitutedaryl, heteroaryl, substituted heteroaryl wherein said carbocycles,heterocycles, aryls, and heteroaryls are further selected frommonocyclic, bicyclic, and tricyclic systems, wherein the bicyclic andtricyclic systems are further selected from fused, non-fused, and spirosystems and wherein said substituents are further selected from —H,-halo, -hydroxyl, —NO₂, —CN, —C₁₋₆ alkyl, —C₁₋₆ alkoxy, —CF₃, —COOR₂,—NR₃R₄; —COR, —COOR, —SO₂, and —SO₂NR₃R₄;and R₃ and R₄ are independently selected from —H, —C₁₋₆ alkyl, —C₁₋₆substituted alkyl, aryl, heteroaryl, substituted aryl, substitutedheteroaryl, and —COOR₂;alternatively R₃ and R₄ are taken together with the adjacent N to form acycle selected from:

with the proviso that only one of R₃ or R₄ can be —COOR₂.

In an aspect of the invention, there is provided a compound, includingpharmaceutically acceptable salts thereof, which is selected from acompound as disclosed in Table 11, Table 12, Table 13, or Table 17.

In an aspect of the invention, there is provided a composition usefulfor treating HIV infection comprising a therapeutic amount of a compoundof Formula I-X and a pharmaceutically acceptable carrier. In an aspectof the invention, the composition further comprises a therapeuticallyeffective amount at least one other agent used for treatment of AIDS orHIV infection selected from nucleoside HIV reverse transcriptaseinhibitors, non-nucleoside HIV reverse transcriptase inhibitors, HIVprotease inhibitors, HIV fusion inhibitors, HIV attachment inhibitors,CCR5 inhibitors, CXCR₄ inhibitors, HIV budding or maturation inhibitors,and HIV integrase inhibitors, and a pharmaceutically acceptable carrier.In an aspect of the invention, the other agent is dolutegravir.

In an aspect of the invention, there is provided a method for treatingHIV infection comprising administering a therapeutically effectiveamount of a compound of Formula I-X, or a pharmaceutically acceptablesalt thereof, to a patient in need thereof. In an aspect of theinvention, the method further comprises administering a therapeuticallyeffective amount of at least one other agent used for treatment of AIDSor HIV infection selected from nucleoside HIV reverse transcriptaseinhibitors, non-nucleoside HIV reverse transcriptase inhibitors, HIVprotease inhibitors, HIV fusion inhibitors, HIV attachment inhibitors,CCR5 inhibitors, CXCR4 inhibitors, HIV budding or maturation inhibitors,and HIV integrase inhibitors. In an aspect of the invention, the otheragent is dolutegravir. In an aspect of the invention, the other agent isadministered to the patient prior to, simultaneously with, orsubsequently to the compound of Formula I-X.

Pharmaceutical Compositions and Methods of Use

The compounds of the invention herein described and set forth aregenerally given as pharmaceutical compositions. These compositions arecomprised of a therapeutically effective amount of a compound of FormulaI or its pharmaceutically acceptable salt, and a pharmaceuticallyacceptable carrier and may contain conventional excipients and/ordiluents. A therapeutically effective amount is that which is needed toprovide a meaningful patient benefit. Pharmaceutically acceptablecarriers are those conventionally known carriers having acceptablesafety profiles. Compositions encompass all common solid and liquidforms, including capsules, tablets, lozenges, and powders, as well asliquid suspensions, syrups, elixirs, and solutions. Compositions aremade using available formulation techniques, and excipients (such asbinding and wetting agents) and vehicles (such as water and alcohols)which are generally used for compositions. See, for example, Remington'sPharmaceutical Sciences, 17th edition, Mack Publishing Company, Easton,Pa. (1985).

Solid compositions which are normally formulated in dosage units andcompositions providing from about 1 to 1000 mg of the active ingredientper dose are preferred. Some examples of dosages are 1 mg, 10 mg, 100mg, 250 mg, 500 mg, and 1000 mg. Generally, other antiretroviral agentswill be present in a unit range similar to agents of that class usedclinically. Typically, this is about 0.25-1000 mg/unit.

Liquid compositions are usually in dosage unit ranges. Generally, theliquid composition will be in a unit dosage range of about 1-100 mg/mL.Some examples of dosages are 1 mg/mL, 10 mg/mL, 25 mg/mL, 50 mg/mL, and100 mg/mL. Generally, other antiretroviral agents will be present in aunit range similar to agents of that class used clinically. Typically,this is about 1-100 mg/mL.

The invention encompasses all conventional modes of administration; oraland parenteral methods are preferred. Generally, the dosing regimen willbe similar to other antiretroviral agents used clinically. Typically,the daily dose will be about 1-100 mg/kg body weight daily. Generally,more compound is required orally and less parenterally. The specificdosing regimen, however, will be determined by a physician using soundmedical judgment.

The compounds of this invention desirably have activity against HIV.Accordingly, another aspect of the invention is a method for treatingHIV infection in a human patient comprising administering atherapeutically effective amount of a compound of Formula I, including apharmaceutically acceptable salt thereof, with a pharmaceuticallyacceptable carrier, excipient and/or diluent.

The invention also encompasses methods where the compound is given incombination therapy. That is, the compound can be used in conjunctionwith, but separately from, other agents useful in treating AIDS and HIVinfection. The compound can also be used in combination therapy whereinthe compound and one or more of the other agents are physically togetherin a fixed-dose combination (FDC). Some of these agents include HIVattachment inhibitors, CCR5 inhibitors, CXCR₄ inhibitors, HIV cellfusion inhibitors, HIV integrase inhibitors, HIV nucleoside reversetranscriptase inhibitors, HIV non-nucleoside reverse transcriptaseinhibitors, HIV protease inhibitors, budding and maturation inhibitors,immunomodulators, and anti-infectives. In these combination methods, thecompound of Formula I will generally be given in a daily dose of about1-100 mg/kg body weight daily in conjunction with other agents. Theother agents generally will be given in the amounts usedtherapeutically. The specific dosing regimen, however, will bedetermined by a physician using sound medical judgment.

“Combination,” “coadministration,” “concurrent” and similar termsreferring to the administration of a compound of Formula I with at leastone anti-HIV agent mean that the components are part of a combinationantiretroviral therapy or HAART as understood by practitioners in thefield of AIDS and HIV infection.

Thus, as set forth above, contemplated herein are combinations of thecompounds of Formula I, together with one or more agents useful in thetreatment of AIDS. For example, the compounds of the invention may beeffectively administered, whether at periods of pre-exposure and/orpost-exposure, in combination with effective amounts of the AIDSantivirals, immunomodulators, anti-infectives, or vaccines, such asthose in the following non-limiting table:

Drug Name Manufacturer Indication ANTIVIRALS Rilpivirine Tibotec HIVinfection, AIDS, ARC (non-nucleoside reverse transcriptase inhibitor)COMPLERA ® Gilead HIV infection, AIDS, ARC; combination withemtricitabine, rilpivirine, and tenofovir disoproxil fumarate 097Hoechst/Bayer HIV infection, AIDS, ARC (non-nucleoside reverse trans-criptase (RT) inhibitor) Amprenavir Glaxo Wellcome HIV infection, 141W94 AIDS, ARC GW 141 (protease inhibitor) Abacavir (1592U89) GlaxoWellcome HIV infection, GW 1592 AIDS, ARC (RT inhibitor) AcemannanCarrington Labs ARC (Irving, TX) Acyclovir Burroughs Wellcome HIVinfection, AIDS, ARC AD-439 Tanox Biosystems HIV infection, AIDS, ARCAD-519 Tanox Biosystems HIV infection, AIDS, ARC Adefovir dipivoxilGilead Sciences HIV infection AL-721 Ethigen ARC, PGL (Los Angeles, CA)HIV positive, AIDS Alpha Interferon Glaxo Wellcome Kaposi's sarcoma, HIVin combination w/Retrovir Ansamycin Adria Laboratories ARC LM 427(Dublin, OH) Erbamont (Stamford, CT) Antibody which Advanced BiotherapyAIDS, ARC Neutralizes pH Concepts Labile alpha aberrant (Rockville, MD)Interferon AR177 Aronex Pharm HIV infection, AIDS, ARC Beta-fluoro-ddANat'l Cancer Institute AIDS-associated diseases CI-1012 Warner-LambertHIV-1 infection Cidofovir Gilead Science CMV retinitis, herpes,papillomavirus Curdlan sulfate AJI Pharma USA HIV infectionCytomegalovirus MedImmune CMV retinitis Immune globin Cytovene SyntexSight threatening Ganciclovir CMV peripheral CMV retinitis DarunavirTibotec-J & J HIV infection, AIDS, ARC (protease inhibitor) DelaviridinePharmacia-Upjohn HIV infection, AIDS, ARC (RT inhibitor) Dextran SulfateUeno Fine Chem. AIDS, ARC, HIV Ind. Ltd. (Osaka, positive Japan)asymptomatic ddC Hoffman-La Roche HIV infection, AIDS, DideoxycytidineARC ddI Bristol-Myers Squibb HIV infection, AIDS, Dideoxyinosine ARC;combination with AZT/d4T DMP-450 AVID HIV infection, (Camden, NJ) AIDS,ARC (protease inhibitor) Efavirenz Bristol Myers Squibb HIV infection,(DMP 266, SUSTIVA ®) AIDS, ARC (-)6-Chloro-4-(S)- (non-nucleoside RTcyclopropylethynyl- inhibitor) 4(S)-trifluoro- methyl-1,4-dihydro-2H-3,1-benzoxazin- 2-one, STOCRINE EL10 Elan Corp, PLC HIV infection(Gainesville, GA) Etravirine Tibotec/J & J HIV infection, AIDS, ARC(non-nucleoside reverse transcriptase inhibitor) Famciclovir Smith Klineherpes zoster, herpes simplex GS 840 Gilead HIV infection, AIDS, ARC(reverse transcriptase inhibitor) HBY097 Hoechst Marion HIV infection,Roussel AIDS, ARC (non-nucleoside reverse transcriptase inhibitor)Hypericin VIMRx Pharm. HIV infection, AIDS, ARC Recombinant Human TritonBiosciences AIDS, Kaposi's Interferon Beta (Almeda, CA) sarcoma, ARCInterferon alfa-n3 Interferon Sciences ARC, AIDS Indinavir Merck HIVinfection, AIDS, ARC, asymptomatic HIV positive, also in combinationwith AZT/ddI/ddC ISIS 2922 ISIS Pharmaceuticals CMV retinitis KNI-272Nat'l Cancer Institute HIV-assoc. diseases Lamivudine, 3TC GlaxoWellcome HIV infection, AIDS, ARC (reverse transcriptase inhibitor);also with AZT Lobucavir Bristol-Myers Squibb CMV infection NelfinavirAgouron HIV infection, Pharmaceuticals AIDS, ARC (protease inhibitor)Nevirapine Boeheringer HIV infection, Ingleheim AIDS, ARC (RT inhibitor)Novapren Novaferon Labs, Inc. HIV inhibitor (Akron, OH) Peptide TPeninsula Labs AIDS Octapeptide (Belmont, CA) Sequence Trisodium AstraPharm. CMV retinitis, HIV Phosphonoformate Products, Inc. infection,other CMV infections PNU-140690 Pharmacia Upjohn HIV infection, AIDS,ARC (protease inhibitor) Probucol Vyrex HIV infection, AIDS RBC-CD4Sheffield Med. HIV infection, Tech (Houston, TX) AIDS, ARC RitonavirAbbott HIV infection, AIDS, ARC (protease inhibitor) SaquinavirHoffmann- HIV infection, LaRoche AIDS, ARC (protease inhibitor)Stavudine; d4T Bristol-Myers Squibb HIV infection, AIDS, Didehydrodeoxy-ARC Thymidine Tipranavir Boehringer Ingelheim HIV infection, AIDS, ARC(protease inhibitor) Valaciclovir Glaxo Wellcome Genital HSV & CMVInfections Virazole Viratek/ICN asymptomatic HIV Ribavirin (Costa Mesa,CA) positive, LAS, ARC VX-478 Vertex HIV infection, AIDS, ARCZalcitabine Hoffmann-LaRoche HIV infection, AIDS, ARC, with AZTZidovudine; AZT Glaxo Wellcome HIV infection, AIDS, ARC, Kaposi'ssarcoma, in combination with other therapies Tenofovir disoproxil,Gilead HIV infection, fumarate salt (VIREAD ®) AIDS, (reversetranscriptase inhibitor) EMTRIVA ® Gilead HIV infection, (Emtricitabine)(FTC) AIDS, (reverse transcriptase inhibitor) COMBIVIR ® GSK HIVinfection, AIDS, (reverse transcriptase inhibitor) Abacavir succinateGSK HIV infection, (or ZIAGEN ®) AIDS, (reverse transcriptase inhibitor)REYATAZ ® Bristol-Myers Squibb HIV infection (or atazanavir) AIDs,protease inhibitor FUZEON ® Roche/Trimeris HIV infection (Enfuvirtide orT-20) AIDs, viral Fusion inhibitor LEXIVA ® GSK/Vertex HIV infection (orFosamprenavir calcium) AIDs, viral protease inhibitor SELZENTRY ™ PfizerHIV infection Maraviroc; (UK 427857) AIDs, (CCR5 antagonist, indevelopment) TRIZIVIR ® GSK HIV infection AIDs, (three drug combination)Sch-417690 (vicriviroc) Schering-Plough HIV infection AIDs, (CCR5antagonist, in development) TAK-652 Takeda HIV infection AIDs, (CCR5antagonist, in development) GSK 873140 GSK/ONO HIV infection (ONO-4128)AIDs, (CCR5 antagonist, in development) Integrase Inhibitor Merck HIVinfection MK-0518 AIDs Raltegravir TRUVADA ® Gilead Combination ofTenofovir disoproxil fumarate salt (VIREAD ®) and EMTRIVA ®(Emtricitabine) Integrase Inhibitor Gilead/Japan Tobacco HIV InfectionGS917/JTK-303 AIDs Elvitegravir in development Triple drug combinationGilead/Bristol-Myers Squibb Combination of Tenofovir ATRIPLA ®disoproxil fumarate salt (VIREAD ®), EMTRIVA ® (Emtricitabine), andSUSTIVA ® (Efavirenz) FESTINAVIR ® Oncolys BioPharma HIV infection AIDsin development CMX-157 Chimerix HIV infection Lipid conjugate of AIDsnucleotide tenofovir GSK1349572 GSK HIV infection Integrase inhibitorAIDs TIVICAY ® dolutegravir IMMUNOMODULATORS AS-101 Wyeth-Ayerst AIDSBropirimine Pharmacia Upjohn Advanced AIDS Acemannan Carrington Labs,Inc. AIDS, ARC (Irving, TX) CL246,738 Wyeth AIDS, Kaposi's Lederle Labssarcoma FP-21399 Fuki ImmunoPharm Blocks HIV fusion with CD4+ cellsGamma Interferon Genentech ARC, in combination w/TNF (tumor necrosisfactor) Granulocyte Genetics Institute AIDS Macrophage Colony SandozStimulating Factor Granulocyte Hoechst-Roussel AIDS Macrophage ColonyImmunex Stimulating Factor Granulocyte Schering-Plough AIDS, MacrophageColony combination Stimulating Factor w/AZT HIV Core Particle RorerSeropositive HIV Immunostimulant IL-2 Cetus AIDS, in combinationInterleukin-2 w/AZT IL-2 Hoffman-LaRoche AIDS, ARC, HIV, inInterleukin-2 Immunex combination w/AZT IL-2 Chiron AIDS, increase inInterleukin-2 CD4 cell counts (aldeslukin) Immune Globulin CutterBiological Pediatric AIDS, in Intravenous (Berkeley, CA) combinationw/AZT (human) IMREG-1 Imreg AIDS, Kaposi's (New Orleans, LA) sarcoma,ARC, PGL IMREG-2 Imreg AIDS, Kaposi's (New Orleans, LA) sarcoma, ARC,PGL Imuthiol Diethyl Merieux Institute AIDS, ARC Dithio CarbamateAlpha-2 Schering Plough Kaposi's sarcoma Interferon w/AZT, AIDSMethionine- TNI Pharmaceutical AIDS, ARC Enkephalin (Chicago, IL) MTP-PECiba-Geigy Corp. Kaposi's sarcoma Muramyl-Tripeptide Granulocyte AmgenAIDS, in combination Colony Stimulating w/AZT Factor Remune ImmuneResponse Immunotherapeutic Corp. rCD4 Genentech AIDS, ARC RecombinantSoluble Human CD4 rCD4-IgG AIDS, ARC hybrids Recombinant Biogen AIDS,ARC Soluble Human CD4 Interferon Hoffman-La Roche Kaposi's sarcoma Alfa2a AIDS, ARC, in combination w/AZT SK&F106528 Smith Kline HIV infectionSoluble T4 Thymopentin Immunobiology HIV infection Research Institute(Annandale, NJ) Tumor Necrosis Genentech ARC, in combination Factor; TNFw/gamma Interferon ANTI-INFECTIVES Clindamycin with Pharmacia Upjohn PCPPrimaquine Fluconazole Pfizer Cryptococcal meningitis, candidiasisPastille Squibb Corp. Prevention of Nystatin Pastille oral candidiasisOrnidyl Merrell Dow PCP Eflornithine Pentamidine LyphoMed PCP treatmentIsethionate (IM & IV) (Rosemont, IL) Trimethoprim AntibacterialTrimethoprim/sulfa Antibacterial Piritrexim Burroughs Wellcome PCPtreatment Pentamidine Fisons Corporation PCP prophylaxis Isethionate forInhalation Spiramycin Rhone-Poulenc Cryptosporidial diarrheaIntraconazole- Janssen-Pharm. Histoplasmosis; R51211 cryptococcalmeningitis Trimetrexate Warner-Lambert PCP Daunorubicin NeXstar, SequusKaposi's sarcoma Recombinant Human Ortho Pharm. Corp. Severe anemiaErythropoietin assoc. with AZT therapy Recombinant Human SeronoAIDS-related Growth Hormone wasting, cachexia Megestrol AcetateBristol-Myers Squibb Treatment of anorexia assoc. W/AIDS TestosteroneAlza, Smith Kline AIDS-related wasting Total Enteral Norwich EatonDiarrhea and Nutrition Pharmaceuticals malabsorption related to AIDS

“Therapeutically effective” means the amount of agent required toprovide a meaningful patient benefit as understood by practitioners inthe field of AIDS and HIV infection. In general, the goals oftherapeutically effective treatment include suppression of viral load,restoration and preservation of immunologic function, improved qualityof life, and reduction of HIV-related morbidity and mortality.

“Patient” means a person infected with the HIV virus and suitable fortherapy as understood by practitioners in the field of AIDS and HIVinfection.

“Treatment,” “therapy,” “regimen,” “HIV infection,” “ARC,” “AIDS” andrelated terms are used as understood by practitioners in the field ofAIDS and HIV infection.

Methods of Synthesis

The compounds of the invention according to the various aspects can bemade by various methods available in the art, including those of thefollowing schemes in the specific examples which follow. The structurenumbering and variable numbering shown in the synthetic schemes may bedistinct from, and should not be confused with, the structure orvariable numbering in the claims or the rest of the specification. Thevariables in the schemes are meant only to illustrate how to make someof the compounds of the invention.

Abbreviations used in the schemes generally follow conventions used inthe art. Some specific chemical abbreviations used in the examples aredefined as follows: “DMF” for N,N-dimethylformamide; “MeOH” formethanol; “Ar” for aryl; “TFA” for trifluoroacetic acid; “BOC” fort-butoxycarbonate, “DMSO” for dimethylsulfoxide; “h” for hours; “rt” forroom temperature or retention time (context will dictate); “min” forminutes; “EtOAc” for ethyl acetate; “THF” for tetrahydrofuran; “Et₂O”for diethyl ether; “DMAP” for 4-dimethylaminopyridine; “DCE” for1,2-dichloroethane; “ACN” for acetonitrile; “DME” for1,2-dimethoxyethane; “HATU” for(1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium3-oxid hexafluorophosphate) “DIEA” for diisopropylethylamine.

Certain other abbreviations as used herein, are defined as follows: “1×”for once, “2×” for twice, “3×” for thrice, “° C.” for degrees Celsius,“eq” for equivalent or equivalents, “g” for gram or grams, “mg” formilligram or milligrams, “L” for liter or liters, “mL” for milliliter ormilliliters, “4” for microliter or microliters, “N” for normal, “M” formolar, “mmol” for millimole or millimoles, “min” for minute or minutes,“h” for hour or hours, “rt” for room temperature, “RT” for retentiontime, “atm” for atmosphere, “psi” for pounds per square inch, “conc.”for concentrate, “sat” or “sat′d” for saturated, “MW” for molecularweight, “mp” for melting point, “ee” for enantiomeric excess, “MS” or“Mass Spec” for mass spectrometry, “ESI” for electrospray ionizationmass spectroscopy, “HR” for high resolution, “HRMS” for high resolutionmass spectrometry, “LCMS” for liquid chromatography mass spectrometry,“HPLC” for high pressure liquid chromatography, “RP HPLC” for reversephase HPLC, “TLC” or “tlc” for thin layer chromatography, “NMR” fornuclear magnetic resonance spectroscopy, “¹H” for proton, “δ” for delta,“s” for singlet, “d” for doublet, “t” for triplet, “q” for quartet, “m”for multiplet, “br” for broad, “Hz” for hertz, and “α”, “β”, “R”, “S”,“E”, and “Z” are stereochemical designations familiar to one skilled inthe art.

EXAMPLES

The following examples illustrate typical syntheses of the compounds ofFormulas I to X, as described generally above. These examples areillustrative only and are not intended to limit the disclosure in anyway. The reagents and starting materials are readily available to one ofordinary skill in the art.

Chemistry

Typical Procedures and Characterization of Selected Examples:

Unless otherwise stated, solvents and reagents were used directly asobtained from commercial sources, and reactions were performed under anitrogen atmosphere. Flash chromatography was conducted on Silica gel 60(0.040-0.063 particle size; EM Science supply). ¹H NMR spectra wererecorded on Bruker DRX-500f at 500 MHz (or Bruker AV 400 MHz, BrukerDPX-300B or Varian Gemini 300 at 300 MHz as stated). The chemical shiftswere reported in ppm on the δ scale relative to δTMS=0. The followinginternal references were used for the residual protons in the followingsolvents: CDCl₃ (δ_(H) 7.26), CD₃OD (δ_(H) 3.30), Acetic-d4 (Acetic Acidd₄) (δ_(H) 11.6, 2.07), DMSO mix or DMSO-D6_CDCl₃ ((_(H) 2.50 and 8.25)(ratio 75%:25%), and DMSO-D6 (δ_(H) 2.50). Standard acronyms wereemployed to describe the multiplicity patterns: s (singlet), br. s(broad singlet), d (doublet), t (triplet), q (quartet), m (multiplet), b(broad), app (apparent). The coupling constant (J) is in Hertz. AllLiquid Chromatography (LC) data were recorded on a Shimadzu LC-10ASliquid chromatograph using a SPD-10AV UV-Vis detector with MassSpectrometry (MS) data determined using a Micromass Platform for LC inelectrospray mode.

Section 1

LCMS Methods:

Method 1

Start % B=0, Final % B=100

Gradient Time=0.5 min hold at 0% B, 0-100% B over 4 min, 0.5 min hold at100% B

Flow Rate=0.5 ml/min

Wavelength=220

Solvent A=5% MeOH—95% H₂O—10 mM Ammonium Acetate

Solvent B=95% MeOH—5% H₂O—10 mM Ammonium Acetate

Column=Waters BEH C18 2.0×50 mm 1.7 um

Method 2

Start % B=30, Final % B=100

Gradient Time=2 min

Flow Rate=0.8 ml/min

Wavelength=220

Solvent A=10% MeOH—90% H₂O—0.1% TFA

Solvent B=90% MeOH-10% H₂O-0.1% TFA

Column=Xbridge C8 2.1×50 mm 2.5 um

Method 3

Start % B=30, Final % B=100

Gradient Time=2 min

Flow Rate=1 ml/min

Wavelength=220

Solvent A=5% MeOH: 95% Water: 10 mM Ammonium Actetate

Solvent B=95% MeOH: 5% Water: 10 mM Ammonium Actetate

Column=Phenomenex LUNA C18, 30×2, 3 u

Method 4

Start % B=30, Final % B=100

Gradient Time=2 min

Flow Rate=1 ml/min

Wavelength=220

Solvent A=10% MeOH-90% H₂O-0.1% TFA

Solvent B=90% MeOH-10% H₂O-0.1% TFA

Column=PHENOMENEX-LUNA 2.0×30 mm 3 um

Method 5

Start % B=0, Final % B=100

Gradient Time=2 min

Flow Rate=1 ml/min

Wavelength=220

Solvent A=10% MeOH-90% H₂O-0.1% TFA

Solvent B=90% MeOH-10% H₂O-0.1% TFA

Column=PHENOMENEX-LUNA 2.0×30 mm 3 um

Method 6

Start % B=30, Final % B=100

Gradient Time=2 min

Flow Rate=8 ml/min

Wavelength=220

Solvent A=10% MeOH-90% H₂O-0.1% TFA

Solvent B=90% MeOH-10% H₂O-0.1% TFA

Column=Xbridge Phenyl 2.1×50 mm 2.5 um

Method 7

Waters Acquity SDS; Run Time: 5.00 min

Solvent Name A: Water; Solvent Name B: Methanol

[Gradient Table] Time(min) Flow Rate % A % B Curve 1 Initial 0.500 100.0 0.00 2 0.50 0.500 100.0  0.00 6 3 4.50 0.500  0.00 100.0 6 4 5.00 0.500 0.00 100.0 6 5 5.02 0.500 100.00  0.00 6 6 5.50 0.500 100.0  0.00Method 8Start % B=0, Final % B=100Gradient Time=2 minFlow Rate=1 ml/minWavelength=220Solvent A=5% MeOH-95% H₂O-10 mM Ammonium AcetateSolvent B=95% MeOH-5% H₂O-10 mM Ammonium AcetateColumn=Phenomenex LUNA C18, 30×2, 3 uMethod 9Start % B=10, Final % B=100Gradient Time=2 minFlow Rate=0.8 ml/minWavelength=220Solvent A=10% MeOH-90% H₂O-0.1% TFASolvent B=90% MeOH-10% H₂O-0.1% TFAColumn=Xbridge Phenyl 2.1×50 mm 2.5 um

PREPARATION OF INTERMEDIATES Intermediate 1: Methyl(S)-4-(5,5,8a-trimethyl-1,2,3,5,8,8a-hexahydroisoquinolin-6-yl)benzoatehydrochloride

Step 1: Preparation of tert-butyl(S)-5,5,8a-trimethyl-6-oxo-3,5,6,7,8,8a-hexahydroisoquinoline-2(1H)-carboxylate

To a solution of(S)-5,5,8a-trimethyl-1,3,5,7,8,8a-hexahydroisoquinolin-6(2H)-one (20.0g, 87 mmol) (prepared as described in J. Med. Chem. 1996, 20, 2302-2312)and Boc₂O (22.8 g, 104 mmol) in CH₂Cl₂ (250 ml) was added Et₃N (24.3 ml,174 mmol) slowly. The reaction mixture was stirred at RT overnight. Thereaction mixture was diluted with CH₂Cl₂ (100 ml), washed with H₂O(2×100 ml) followed by brine (100 ml), dried over Na₂SO₄, andconcentrated in vacuo. The crude product was purified by silica gelcolumn eluted with 20% EtOAc/hexanes to give the desired product (25.0g, 98%) as a solid. ¹H NMR (400 MHz, CHLOROFORM-d) δ 5.61-5.43 (m, 1H),4.44-4.13 (m, 1H), 3.97-3.72 (m, 1H), 3.70-3.55 (m, 1H), 2.76-2.43 (m,3H), 1.86-1.69 (m, 2H), 1.49 (s, 9H), 1.26 (s, 6H), 1.09 (s, 3H).

Step 2: Preparation of tert-butyl(S)-5,5,8a-trimethyl-6-(((trifluoromethyl)sulfonyl)oxy)-3,5,8,8a-tetrahydroisoquinoline-2(1H)-carboxylate

To a solution of tert-butyl(S)-5,5,8a-trimethyl-6-oxo-3,5,6,7,8,8a-hexahydroisoquinoline-2(1H)-carboxylate(25.0 g, 85 mmol) in THF (300 ml) at −78° C. was added KHMDS (0.5M intoluene) (341 ml, 170 mmol). The yellow-orange solution was stirred at−78° C. for 1 h. A solution of N-phenylbis-(trifluoromethanesulfonamide) (33.5 g, 94 mmol) in THF (120 ml) wasadded. The resulted reaction mixture was stirred at −78° C. for 2 h,then warmed to RT and stirred overnight. The reaction was quenched withH₂O (500 ml). The separated aqueous layer was extracted with EtOAc(3×250 ml). The combined organic layers were washed with brine (250 ml),dried over MgSO₄, and concentrated in vacuo. The crude product waspurified by silica gel column eluted with 20% EtOAc/hexanes to give thedesired product (20.6 g, 57%) as an oil. ¹H NMR (400 MHz, CHLOROFORM-d)δ 5.79 (dd, J=6.0, 3.3 Hz, 1H), 5.69-5.56 (m, 1H), 4.45-4.17 (m, 1H),4.01-3.78 (m, 1H), 3.75-3.58 (m, 1H), 2.76-2.54 (m, 1H), 2.09-2.01 (m,2H), 1.49 (s, 9H), 1.30 (s, 3H), 1.27 (br. s., 3H), 1.20 (s, 3H).

Step 3: Preparation of tert-butyl(S)-6-(4-(methoxycarbonyl)phenyl)-5,5,8a-trimethyl-3,5,8,8a-tetrahydroisoquinoline-2(1H)-carboxylate

To a solution of tert-butyl(S)-5,5,8a-trimethyl-6-(((trifluoromethyl)sulfonyl)oxy)-3,5,8,8a-tetrahydroisoquinoline-2(1H)-carboxylate(20.6 g, 48.4 mmol) in dioxane (250 ml) was added Na₂CO₃ (15.4 g, 145mmol) in H₂O (50 ml), (4-(methoxycarbonyl)phenyl)boronic acid (11.3 g,63 mmol) and Pd(Ph₃P)₄ (2.8 g, 2.42 mmol). The resulted mixture wasrefluxed under nitrogen for 4 h. The reaction mixture was diluted withH₂O (250 ml), extracted with ethyl acetate (3×250 ml). The combinedorganic layers were dried over Na₂SO₄, and concentrated in vacuo. Thecrude product was purified by silica gel column eluted with 5%EtOAc/hexanes to give the desired product (13.4 g, 67%) as a solid. ¹HNMR (400 MHz, CHLOROFORM-d) δ 7.97 (d, J=8.3 Hz, 2H), 7.24 (d, J=8.5 Hz,2H), 5.68-5.50 (m, 2H), 4.46-4.19 (m, 1H), 3.93 (s, 3H), 3.91-3.64 (m,2H), 2.78-2.60 (m, 1H), 2.01 (br. s., 2H), 1.50 (s, 9H), 1.23 (s, 3H),1.20 (s, 3H), 1.11 (s, 3H).

Step 4

To a solution of tert-butyl(S)-6-(4-(methoxycarbonyl)phenyl)-5,5,8a-trimethyl-3,5,8,8a-tetrahydroisoquinoline-2(1H)-carboxylate(7.7 g, 18.7 mmol) in dioxane (100 ml) was added HCl (4M in dioxane)(23.4 ml, 94 mmol) and the mixture was stirred at RT for 2 days. Hexanes(100 ml) was added into the reaction mixture. The white solid wascollected by filtration, washed with hexanes (2×50 ml), and dried undervacuum to give the title compound (5.93 g, 91%) as HCl salt. ¹H NMR (400MHz, METHANOL-d₄) δ 7.98 (d, J=8.3 Hz, 2H), 7.31 (d, J=8.3 Hz, 2H), 5.81(dd, J=3.8, 2.8 Hz, 1H), 5.56 (dd, J=5.8, 3.0 Hz, 1H), 3.91 (s, 3H),3.77 (qd, J=16.7, 3.1 Hz, 2H), 3.33 (d, J=12.5 Hz, 1H), 3.05 (d, J=12.5Hz, 1H), 2.19-2.14 (m, 2H), 1.48 (s, 3H), 1.24 (s, 3H), 1.23 (s, 3H).

Intermediate 2: Methyl(S)-4-(5,5,8a-trimethyl-2-(4-phenylpiperidine-4-carbonyl)-1,2,3,5,8,8a-hexahydroisoquinolin-6-yl)benzoatehydrochloride

Step 1: Preparation of tert-butyl(S)-4-(6-(4-(methoxycarbonyl)phenyl)-5,5,8a-trimethyl-1,2,3,5,8,8a-hexahydroisoquinoline-2-carbonyl)-4-phenylpiperidine-1-carboxylate

To a solution of methyl(S)-4-(5,5,8a-trimethyl-1,2,3,5,8,8a-hexahydroisoquinolin-6-yl)benzoatehydrochloride (1.82 g, 5.2 mmol) and1-(tert-butoxycarbonyl)-4-phenylpiperidine-4-carboxylic acid (1.92 g,6.3 mmol) in CH₂Cl₂ (100 ml) was added DIPEA (9 ml, 52 mmol) followed byHATU (2.98 g, 7.9 mmol). The resulted solution was stirred at RT for 3h. The reaction mixture was diluted with CH₂Cl₂ (150 ml) and washed withH₂O (2×100 ml) followed by brine (100 ml), dried over Na₂SO₄ andconcentrated in vacuo. The crude product was purified by silica gelcolumn eluted with 20% EtOAc/hexane to give the desired product (2.88 g,92%) as a solid.

LC/MS m/z 621.40 (M+Na)⁺, 2.71 min (Method 2).

Step 2

To a solution of tert-butyl(S)-4-(6-(4-(methoxycarbonyl)phenyl)-5,5,8a-trimethyl-1,2,3,5,8,8a-hexahydroisoquinoline-2-carbonyl)-4-phenylpiperidine-1-carboxylate(2.88 g, 4.8 mmol) in dioxane (30 ml) was added HCl (4M in 1,4-dioxane)(6 ml, 24 mmol) and the mixture was stirred at RT overnight. Thereaction mixture was concentrated in vacuo, and the residue wastriturated with ether. The ether was decanted and residue wasconcentrated in vacuo to give the title compound (2.53 g, 98%) as HClsalt without purification. LC/MS m/z 499.35 (M+H)⁺, 2.18 min (Method 2).

Intermediate 3: Methyl(S)-4-(2-(2-formylbenzoyl)-5,5,8a-trimethyl-1,2,3,5,8,8a-hexahydroisoquinolin-6-yl)benzoate

Step 1: Preparation of 2-formylbenzoyl Chloride

To a solution of 2-formylbenzoic acid (210 mg, 1.4 mmol) in CH₂Cl₂ (10ml) at 0° C. was added oxalyl chloride (2M in DCM) (0.7 ml, 1.4 mmol)followed by DMF (11 μl, 0.14 mmol). The reaction mixture was warmed toRT and stirred overnight. The reaction mixture was concentrated in vacuoto give the crude product.

Step 2

To a solution of methyl(S)-4-(5,5,8a-trimethyl-1,2,3,5,8,8a-hexahydroisoquinolin-6-yl)benzoatehydrochloride (400 mg, 1.15 mmol) in CH₂Cl₂ (10 ml) was added TEA (0.24ml, 1.73 mmol) followed by crude 2-formylbenzoyl chloride. The reactionmixture was stirred at 0° C. for 2 h then warmed to RT and stirred for 3days (over weekend). The reaction mixture was concentrated in vacuo. Thecrude product was purified by silica gel column eluted with 35%EtOAc/hexanes to give the desired product (403 mg, 79%) as a solid.LC/MS m/z 444.25 (M+H)⁺, 2.47 min (Method 2).

Example 1 Preparation of(S)-4-(2-benzoyl-5,5,8a-trimethyl-1,2,3,5,8,8a-hexahydroisoquinolin-6-yl)benzoicacid

Step 1: Preparation of methyl(S)-4-(2-benzoyl-5,5,8a-trimethyl-1,2,3,5,8,8a-hexahydroisoquinolin-6-yl)benzoate

To a solution of methyl(S)-4-(5,5,8a-trimethyl-1,2,3,5,8,8a-hexahydroisoquinolin-6-yl)benzoatehydrochloride (30 mg, 0.096 mmol) in CH₂Cl₂ (2 ml) was added benzoylchloride (16 mg, 0.12 mmol), Et3N (0.13 ml, 0.96 mmol) and DMAP (1.2 mg,9.6 μmop. The resulted mixture was stirred at RT for 3 h. The reactionwas quenched with 1N HCl (1 ml) and the mixture was extracted withCH₂Cl₂ (2 ml). The organic layer was washed with brine (2 ml) thenconcentrated in vacuo to give the crude product without purification.LC/MS m/z 416.02 (M+H)⁺, 2.48 min (Method 2).

Step 2

To a solution of crude methyl(S)-4-(2-benzoyl-5,5,8a-trimethyl-1,2,3,5,8,8a-hexahydroisoquinolin-6-yl)benzoateindioxane (2 ml) and MeOH (1 ml) was added 1N NaOH (1 ml). The mixture wasstirred at 50° C. for 2 h. The reaction mixture was purified by PrepHPLC to give the desired product (22 mg, 56%) as a solid. ¹H NMR (300MHz, DMSO-d6, 100° C.) δ 7.90 (d, J=8.1 Hz, 2H), 7.50-7.37 (m, 5H), 7.29(d, J=6.6 Hz, 2H), 5.69 (br. s., 1H), 5.54 (dd, J=6.4, 2.7 Hz, 1H), 3.90(d, J=17.9 Hz, 2H), 2.95 (d, J=12.4 Hz, 2H), 2.12-1.96 (m, 2H), 1.24 (s,3H), 1.19 (s, 3H), 1.13 (s, 3H).

LC/MS m/z 402.24 (M+H)⁺, 2.34 min (Method 2).

The examples in Table 1 were prepared from intermediate 1 by theprocedure described for the preparation of Example 1 using the reagentindicated in the table instead of benzoyl chloride:

TABLE 1 Ex Reagent MW Obs (M + 1)⁺ RT Met  2 3-fluorobenzoyl chloride419.2 420.22 2.46 2  3 4-fluorobenzoyl chloride 419.2 420.28 2.43 2  42,3-difluorobenzoyl 437.2 438.26 2.46 2 chloride  5 2,4-difluorobenzoyl437.2 438.33 2.45 2 chloride  6 2,5-difluorobenzoyl 437.2 438.33 2.41 2chloride  7 3,4-difluorobenzoyl 437.2 438.26 2.45 2 chloride  83,5-difluorobenzoyl 437.2 438.19 2.46 2 chloride  9 oxalyl chloride648.3 649.4  2.75 6 10 oxalyl chloride 369.2 370.3  1.33 8 Ex = Example;MW = Molecular weight; Obs = Observed; RT = Retention time; Met = LC/MSMethod.

Example 11 Preparation of(S)-4-(2-(2-(4-(tert-butoxycarbonyl)piperazin-1-yl)benzoyl)-5,5,8a-trimethyl-1,2,3,5,8,8a-hexahydroisoquinolin-6-yl)benzoicacid

Step 1: Preparation of tert-butyl(S)-4-(2-(6-(4-(methoxycarbonyl)phenyl)-5,5,8a-trimethyl-1,2,3,5,8,8a-hexahydroisoquinoline-2-carbonyl)phenyl)piperazine-1-carboxylate

To a solution of methyl(S)-4-(5,5,8a-trimethyl-1,2,3,5,8,8a-hexahydroisoquinolin-6-yl)benzoatehydrochloride (30 mg, 0.086 mmol) and2-(4-(tert-butoxycarbonyl)piperidin-1-yl)benzoic acid (40 mg, 0.13 mmol)in CH₂Cl₂ (2 ml) was added DIPEA (0.15 ml, 0.86 mmol) followed by HATU(49 mg, 0.13 mmol). The resulted solution was stirred at RT for 2 h. Thesolvent was evaporated to give the crude product without purification.

LC/MS m/z 600.47 (M+H)⁺, 2.48 min (Method 2).

Step 2

To a solution of crude tert-butyl(S)-4-(2-(6-(4-(methoxycarbonyl)phenyl)-5,5,8a-trimethyl-1,2,3,5,8,8a-hexahydroisoquinoline-2-carbonyl)phenyl)piperazine-1-carboxylatein dioxane (2 ml) and MeOH (1 ml) was added 1N NaOH (1 ml). The mixturewas stirred at 50° C. for 3 h. The reaction mixture was purified by PrepHPLC to give the desired product (27 mg, 53%) as a solid. LC/MS m/z586.317 (M+H)⁺, 2.20 min (Method 2).

The examples in Table 2 were prepared from intermediate 1 by theprocedure described for the preparation of Example 11 using the reagentindicated in the table instead of2-(4-(tert-butoxycarbonyl)piperidin-1-yl)benzoic acid:

TABLE 2 Ex Reagent MW Obs (M + 1)⁺ RT Met 12 isophthalic acid 445.2446.34 1.76 2 13 terephthalic acid 445.2 445.86 1.72 2 14 phthalic acid445.2 446.24 2.63 2 15 (1S,4S)-4-(tert- 522.3 523.49 2.52 2butoxycarbonylamino)cyclo- hexanecarboxylic acid 16 (1R,4R)-4-(tert-522.3 523.49 2.47 2 butoxycarbonylamino)cyclo- hexanecarboxylic acid 172-methoxybenzoic acid- 431.2 432.29 2.77 3 18 3-methoxybenzoic acid431.2 432.29 2.82 2 19 4-methoxybenzoic acid 431.2 432.29 2.8  2 202-carbamoylbenzoic acid 444.2 449.28 2.72 2 (M- H₂O + Na)⁺ 213-carbamoylbenzoic acid 444.2 445.28 2.51 2 22 4-carbamoylbenzoic acid444.2 445.28 2.52 2 23 2-(dimethylamino)benzoic acid 444.2 445.28 2.64 224 3-(dimethylamino)benzoic acid 444.2 445.28 2.57 2 254-(dimethylamino)benzoic acid 444.2 445.34 2.64 2 26 2-morpholinobenzoicacid 486.3 487.29 2.74 2 27 3-morpholinobenzoic acid 486.3 487.29 2.68 228 4-morpholinobenzoic acid 486.3 487.29 2.64 2 293-(4-methylpiperazin-1- 499.3 500.35 2.36 2 yl)benzoic acid 304-(4-methylpiperazin-1- 499.3 500.35 2.32 2 yl)benzoic acid 31 4-((1,1-548.2 549.34 2.35 2 dioxidothiomorpholino)methyl) benzoic acid 325-(benzylsulfonyl)-2- 585.2 586.17 2.55 2 methoxybenzoic acid 334-(((tert- 530.3 531.37 2.68 2 butoxycarbonyl)amino)methyl) benzoic acid34 3-(dimethylamino)propanoic 396.2 397.26 2.06 2 acid hydrochloride 352-(dimethylamino)acetic acid 382.2 384.41 2.03 2 hydroxychloride 363-(1,1- 486.2 487.25  1.687 6 dioxidothiomorpholino) propanoic acid 372-(1,1- 472.2 473.25  1.788 6 dioxidothiomorpholino)acetic acid 383-((1,1- 548.2 549.17 1.55 4 dioxidothiomorpholino)methyl) benzoic acid39 1H-indole-6-carboxylic acid 440.2 441.2  1.59 3 401H-benzo[d]imidazole-5- 441.2 442.2  1.21 3 carboxylic acid 412-methyl-1H- 455.2 456.3  1.28 3 benzo[d]imidazole-5- carboxylic acid 421H-benzo[d][1,2,3]triazole-5- 442.2 443.2  1.19 3 carboxylic acid 431H-indole-5-carboxylic acid 440.2 463.31 2.6  2 (M + Na)⁺ 442-(4-(2-(1,1- 646.3 647.34 2.92 2 dioxidothiomorpholino)ethyl)piperazin-1-yl)benzoic acid 45 pyridine-3,5-dicarboxylic acid 446.2447.22 1.59 4 46 1-(tert-butoxycarbonyl)-4- 584.3 583.5  2.08 3phenylpiperidine-4-carboxylic (M − 1)⁻ acid 47 4-benzyl-1-(tert- 598.3597.6  2.06 3 butoxycarbonyl)piperidine-4- (M − 1)⁻ carboxylic acid 481-(tert-butoxycarbonyl)-4- 522.3 523.31 4.01 7methylpiperidine-4-carboxylic acid 49 1-(tert-butoxycarbonyl)-4- 550.3551.34 4.23 7 isopropylpiperidine-4- carboxylic acid 501-(tert-butoxycarbonyl)-4- 590.4 591.37 4.49 7 cyclohexylpiperidine-4-carboxylic acid Ex = Example; MW = Molecular weight; Obs = Observed; RT= Retention time; Met = LC/MS Method.

Example 51 Preparation of(S)-4-(5,5,8a-trimethyl-2-(2-(piperazin-1-yl)benzoyl)-1,2,3,5,8,8a-hexahydroisoquinolin-6-yl)benzoicacid

To a solution of(S)-4-(2-(2-(4-(tert-butoxycarbonyl)piperazin-1-yl)benzoyl)-5,5,8a-trimethyl-1,2,3,5,8,8a-hexahydroisoquinolin-6-yl)benzoicacid (25 mg, 0.043 mmol) in CH₂Cl₂ (2 ml) was added TFA (0.5 ml). Theresulted solution was stirred at RT for 30 min. The reaction mixture wasconcentrated in vacuo. The crude product was purified by Prep HPLC togive the desired product (20 mg, 94%) as a solid. LC/MS m/z 486.38(M+H)⁺, 2.27 min (Method 2).

The examples in Table 3 were prepared by the procedure described inExample 51 using the using the starting materials indicated in the tableinstead ofS)-4-(2-(2-(4-(tert-butoxycarbonyl)piperazin-1-yl)benzoyl)-5,5,8a-trimethyl-1,2,3,5,8,8a-hexahydroisoquinolin-6-yl)benzoicacid:

TABLE 3 Obs Ex Reagent MW M + 1 RT Met 52 4-((S)-2-((1R,2S)-4-((tert-422.3 421.3  0.9  3 butoxycarbonyl)amino)cyclohexane-1- (M − 1)⁻carbonyl)-5,5,8a-trimethyl-1,2,3,5,8,8a-hexahydroisoquinolin-6-yl)benzoic acid 53 (S)-4-(2-(4-(((tert- 430.2431.33 2.37  2 butoxycarbonyl)amino)methyl)benzoyl)5,5,8a-trimethyl-1,2,3,5,8,8a- hexahydroisoquinolin-6-yl)benzoic acid 54(S)-4-(2-(1-(tert-butoxycarbonyl)-4- 484.3 485.35 2.021 6phenylpiperidine-4-carbonyl)-5,5,8a- trimethyl-1,2,3,5,8,8a-hexahydroisoquinolin-6-yl)benzoic acid 55 (S)-4-(2-(4-benzyl-1-(tert-498.3 499.35 2.035 6 butoxycarbonyl)piperidine-4-carbonyl)-5,5,8a-trimethyl-1,2,3,5,8,8a- hexahydroisoquinolin-6-yl)benzoic acid 564-((S)-2-(1-((tert-butoxycarbonyl)-L- 597.4 598.35 2.36  6leucyl)-4-phenylpiperidine-4-carbonyl)- 5,5,8a-trimethyl-1,2,3,5,8,8a-hexahydroisoquinolin-6-yl)benzoic acid 574-((S)-2-(1-((tert-butoxycarbonyl)-D- 597.4 598.35 2.36  6leucyl)-4-phenylpiperidine-4-carbonyl)- 5,5,8a-trimethyl-1,2,3,5,8,8a-hexahydroisoquinolin-6-yl)benzoic acid Ex = Example; MW = Molecularweight; Obs = Observed; RT = Retention time; Met = LC/MS Method.

Example 58 Preparation of4,4′-((8aS,8a′S)-isophthaloylbis(5,5,8a-trimethyl-1,2,3,5,8,8a-hexahydroisoquinoline-2,6-diyl))dibenzoicacid

Step 1: Preparation of dimethyl4,4′-((8aS,8a'S)-isophthaloylbis(5,5,8a-trimethyl-1,2,3,5,8,8a-hexahydroisoquinoline-2,6-diyl))dibenzoate

To a solution of methyl(S)-4-(5,5,8a-trimethyl-1,2,3,5,8,8a-hexahydroisoquinolin-6-yl)benzoatehydrochloride (50 mg, 0.16 mmol) and isophthalic acid (13 mg, 0.08 mmol)in CH₂Cl₂ (2 ml) was added DIPEA (0.14 ml, 0.80 mmol) followed by HATU(92 mg, 0.24 mmol). The resulted solution was stirred at RT for 2 h. Thereaction mixture was concentrated in vacuo to give crude product withoutpurification. LC/MS m/z 753.30 (M+H)⁺, 2.41 min (Method 2).

Step 2

To a solution of crude dimethyl4,4′-((8aS,8a'S)-isophthaloylbis(5,5,8a-trimethyl-1,2,3,5,8,8a-hexahydroisoquinoline-2,6-diyl))dibenzoatein dioxane (5 ml) was added 1N NaOH (1 ml). The mixture was stirred at50° C. for 4 h. The reaction mixture was purified by Prep HPLC to givethe desired product (16 mg, 24%) as a solid. LC/MS m/z 725.26 (M+H)⁺,2.17 min (Method 2).

The examples in Table 4 were prepared from intermediate 1 by theprocedure described in Example 58 using the reagents indicated in Table4:

TABLE 4 Obs Ex Reagent MW (M + 1)⁺ RT Met 59 terephthalic acid 724.4725.19 2.22 2 60 phthalic acid 724.4 725.19 2.55 2 61pyridine-2,6-dicarboxylic acid 725.4 726.4  2.35 5 62thiophene-2,5-dicarboxylic acid 730.3 731.36 2.37 5 63pyridine-3,5-dicarboxylic acid 725.4 726.38 2.35 5 64thiophene-3,4-dicarboxylic acid 730.3 731.49 2.14 4 65bicyclo[2.2.1]heptane-2,3- 742.4 743.7  1.73 3 dicarboxylic acid Ex =Example; MW = Molecular weight; Obs = Observed; RT = Retention time; Met= LC/MS Method.

Example 66 Preparation of(S)-4-(2-(3-(1,1-dioxidothiomorpholine-4-carbonyl)benzoyl)-5,5,8a-trimethyl-1,2,3,5,8,8a-hexahydroisoquinolin-6-yl)benzoicacid

Step 1: Preparation of(S)-3-(6-(4-(methoxycarbonyl)phenyl)-5,5,8a-trimethyl-1,2,3,5,8,8a-hexahydroisoquinoline-2-carbonyl)benzoicacid

To a solution of methyl(S)-4-(5,5,8a-trimethyl-1,2,3,5,8,8a-hexahydroisoquinolin-6-yl)benzoatehydrochloride (50 mg, 0.144 mmol) and isophthalic acid (48 mg, 0.29mmol) in CH₂Cl₂ (5 ml) was added DIPEA (0.13 ml, 0.72 mmol) followed byHATU (164 mg, 0.43 mmol). The resulted solution was stirred at RT for 3h. The reaction mixture was diluted with CH₂Cl₂ (5 ml), washed withNaHCO₃(5 ml) followed by brine (5 ml), dried over Na₂SO₄, andconcentrated in vacuo to give crude product without purification.

LC/MS m/z 460.30 (M+H)⁺, 1.70 min (Method 3).

Step 2: Preparation of methyl(S)-4-(2-(3-((3-(1,1-dioxidothiomorpholino)propyl)carbamoyl)benzoyl)-5,5,8a-trimethyl-1,2,3,5,8,8a-hexahydroisoquinolin-6-yl)benzoate

To a solution of crude(S)-3-(6-(4-(methoxycarbonyl)phenyl)-5,5,8a-trimethyl-1,2,3,5,8,8a-hexahydroisoquinoline-2-carbonyl)benzoicacid and 4-(3-aminopropyl)thiomorpholine 1,1-dioxide (41 mg, 0.215 mmol)in CH₂Cl₂ (5 ml) was added DIPEA (0.125 ml, 0.72 mmol) followed by HATU(82 mg, 0.215 mmol). The resulted solution was stirred at RT for 2 h.The reaction mixture was diluted with CH₂Cl₂ (10 ml), washed with H₂O(10 ml) followed by brine (10 ml), dried over Na₂SO₄, and concentratedin vacuo to give crude product without purification. LC/MS m/z 634.45(M+H)⁺, 2.09 min (Method 2).

Step 3

To a solution of crude methyl(S)-4-(2-(3-((3-(1,1-dioxidothiomorpholino)propyl)carbamoyl)benzoyl)-5,5,8a-trimethyl-1,2,3,5,8,8a-hexahydroisoquinolin-6-yl)benzoatein dioxane (2 ml) and MeOH (1 ml) was added 1N NaOH (1 ml). The mixturewas stirred at 50° C. for 4 h. The reaction mixture was purified by PrepHPLC to give the desired product (39 mg, 42%) as a solid. ¹H NMR (400MHz, METHANOL-d4) δ 8.00-7.91 (m, 4H), 7.67-7.58 (m, 2H), 7.27 (t, J=8.2Hz, 2H), 5.85-5.80 (m, 0.5H), 5.62-5.56 (m, 1H), 5.53-5.47 (m, 0.5H),4.85-4.77 (m, 0.5H), 4.50 (d, J=12.5 Hz, 0.5H), 4.16-4.07 (m, 0.5H),3.95-3.84 (m. 0.5H), 3.66-3.59 (m, 4H), 3.51 (t, J=6.5 Hz, 2H),3.46-3.40 (m, 4H), 3.32-3.24 (m, 1H), 3.21-3.12 (m, 2.5H), 2.93-2.85 (m,0.5H), 2.19-2.13 (m, 1H), 2.06-1.96 (m, 2.5H), 1.86-1.78 (m, 0.5H), 1.35(s, 1.5H), 1.27 (s, 1.5H), 1.22 (s, 1.5H), 1.18 (s, 1.5H), 1.16 (s,1.5H), 1.12 (s, 1.5H). LC/MS m/z 620.40 (M+H)⁺, 1.84 min (Method 2).

The examples in Table 5 were prepared from intermediate 1 by theprocedure described in Example 66 using the reagents indicated in thetable:

TABLE 5 Obs Ex Reagent MW (M + 1)⁺ RT Met 67 phthalic acid followed by562.2 563.3 2.52  2 thiomorpholine 1,1-dioxide 68 isophthalic acidfollowed by 562.2 563.37 2.51  2 thiomorpholine 1,1-dioxide 69terephthalic acid followed by 562.2 563.37 2.5  2 thiomorpholine1,1-dioxide 70 pyridine-2,6-dicarboxylic acid 620.3 621.27 1.34  4 71pyridine-3,5-dicarboxylic acid 620.3 621.4  1.32  4 72thiophene-2,5-dicarboxylic acid 625.2 626.26 1.41  4 73thiophene-3,4-dicarboxylic acid 625.2 626.35 1.875 6 Ex = Example; MW =Molecular weight; Obs = Observed; RT = Retention time; Met = LC/MSMethod.

Example 74 Preparation of(S)-4-(2-(4-((3-(1,1-dioxidothiomorpholino)propyl)amino)-1,3,5-triazin-2-yl)-5,5,8a-trimethyl-1,2,3,5,8,8a-hexahydroisoquinolin-6-yl)benzoicacid

Step 1: Preparation of methyl(S)-4-(2-(4-chloro-1,3,5-triazin-2-yl)-5,5,8a-trimethyl-1,2,3,5,8,8a-hexahydroisoquinolin-6-yl)benzoate

In a sealed tube, a suspension of methyl(S)-4-(5,5,8a-trimethyl-1,2,3,5,8,8a-hexahydroisoquinolin-6-yl)benzoatehydrochloride (50 mg, 0.144 mmol), 2,4-dichloro-1,3,5-triazine (43 mg,0.287 mmol), K₃PO₄ (122 mg, 0.575 mmol) and NaI (43 mg, 0.287 mmol) inMeCN (5 ml) was heated at 125° C. overnight. The reaction mixture wascooled to RT, diluted with CH₂Cl₂ (20 ml), washed with H₂O (20 ml),dried over Na₂SO₄, and concentrated. The crude product was purified bysilica gel column eluted with 10% Hex/EtOAc) to give the desired product(33 mg, 54%) as a solid. ¹H NMR (400 MHz, CHLOROFORM-d) δ 8.38 (d, J=9.3Hz, 1H), 7.98 (d, J=8.3 Hz, 2H), 7.24 (d, J=8.5 Hz, 2H), 5.69-5.66 (m,1H), 5.58 (dt, J=5.1, 3.7 Hz, 1H), 4.80 (dt, J=18.6, 4.1 Hz, 1H), 4.61(dd, J=17.8, 12.8 Hz, 1H), 3.93 (s, 3H), 3.93-3.86 (m, 1H), 2.93 (dd,J=12.7, 9.2 Hz, 1H), 2.14-2.09 (m, 2H), 1.25 (s, 3H), 1.23 (s, 1.5H),1.22 (s, 1.5H), 1.13 (s, 1.5H), 1.12 (s, 1.5H). LC/MS m/z 425.22 (M+H)⁺,2.93 min (Method 2).

Step 2: Preparation of methyl(S)-4-(2-(4-((3-(1,1-dioxidothiomorpholino)propyl)amino)-1,3,5-triazin-2-yl)-5,5,8a-trimethyl-1,2,3,5,8,8a-hexahydroisoquinolin-6-yl)benzoate

In a sealed tube, a suspension of methyl(S)-4-(2-(4-chloro-1,3,5-triazin-2-yl)-5,5,8a-trimethyl-1,2,3,5,8,8a-hexahydroisoquinolin-6-yl)benzoate(33 mg, 0.078 mmol), 4-(3-aminopropyl)thiomorpholine 1,1-dioxide (30 mg,0.155 mmol), K3PO4 (66 mg, 0.311 mmol) and NaI (23 mg, 0.155 mmol) inDMF (5 ml) was heated at 125° C. The reaction mixture was cooled to RT,diluted with CH₂Cl₂ (20 ml), washed with H₂O (20 ml), dried over Na₂SO₄,and concentrated in vacuo to give crude product as solid. LC/MS m/z581.33 (M+H)⁺, 2.77 min (Method 2).

TABLE 6 Obs Ex Reagent MW (M + 1)⁺ RT Met 75 2,4-dichloro-1,3,5-triazine671.4 672.34 2.19  4 76 2,6-dibromopyridine, step 1 and 452.1 453.143.68  2 step 3 77 2,5-dibromothiazole, step 1 and 458.1 459.2  2.484 6step 3 78 2,5-dibromothiazole, step 1 and 380.2 381.25 1.745 6 step 3 794-(2-chloroethyl)thiomorpholine 458.2 459.22 2.66  7 1,1-dioxide, step 1and step 3 80 2-bromobenzo[d]thiazole 430.2 431.17 4.28  7 81 methyl(S)-4-(2-(2-(1H- 678.3 679.3  2.13  6 benzo[d]imidazol-2-yl)benzoyl)-5,5,8a-trimeethyl-1,2,3,5,8,8a- hexahydroisoquinolin-6- tl)benzoate and4-(2- chloroethyl)thiomorpholine 1,1- dioxide 82 methyl (S)-4-(2-(2-(1H-840.4 858.35 2.39  6 benzo[d]imidazol-2-yl)benzoyl)- (M + MH4)⁺5,5,8a-trimethyl-1,2,3,5,8,8a- hexahydroisoquinolin-6- yl)benzoate and4-(2- chloroethyl)thiomorpholine 1,1- dioxide Ex = Example; MW =Molecular weight; Obs = Observed; RT = Retention time; Met = LC/MSMethod.

Step 3

To a solution of crude methyl(S)-4-(2-(4-((3-(1,1-dioxidothiomorpholino)propyl)amino)-1,3,5-triazin-2-yl)-5,5,8a-trimethyl-1,2,3,5,8,8a-hexahydroisoquinolin-6-yl)benzoatein dioxane (2 ml) and MeOH (1 ml) was added 1N NaOH (1 ml). The mixturewas stirred at 50° C. for 2 h. The reaction mixture was purified by PrepHPLC to give the desired product (40 mg, 84%) as a solid. ¹H NMR (400MHz, METHANOL-d4) δ 8.31 (d, J=4.5 Hz, 1H), 7.96 (d, J=8.3 Hz, 2H), 7.28(d, J=8.3 Hz, 2H), 5.79 (t, J=3.0 Hz, 1H), 5.59 (t, J=3.9 Hz, 1H), 4.86(t, J=3.8 Hz, 1H), 4.65 (dd, J=12.7, 8.2 Hz, 1H), 4.07-3.95 (m, 1H),3.69-3.54 (m, 6H), 3.49-3.40 (m, 4H), 3.23-3.18 (m, 2H), 3.06 (dd,J=12.7, 8.9 Hz, 1H), 2.20-2.01 (m, 4H), 1.30-1.22 (m, 6H), 1.14 (s, 3H).LC/MS m/z 567.30 (M+H)⁺, 2.52 min (Method 2).

The examples in Table 6 were prepared from intermediate 1 by theprocedure described in Example 74 using the reagents indicated in thetable:

Table 6

Ex=Example; MW=Molecular weight; Obs=Observed; RT=Retention time;Met=LC/MS Method.

Examples 83 Preparation of4-((8aS)-2-(2-(4-(tert-butoxycarbonyl)piperazin-1-yl)benzoyl)-5,5,8a-trimethyldecahydroisoquinolin-6-yl)benzoicacid

Step 1: Preparation of a Mixture of methyl4-((8aS)-5,5,8a-trimethyl-1,2,3,5,6,7,8,8a-octahydroisoquinolin-6-yl)benzoatehydrochloride and methyl4-((8aS)-5,5,8a-trimethyl-1,2,3,4,4a,5,8,8a-octahydroisoquinolin-6-yl)benzoatehydrochloride

To a solution of methyl(S)-4-(5,5,8a-trimethyl-1,2,3,5,8,8a-hexahydroisoquinolin-6-yl)benzoatehydrochloride (100 mg, 0.29 mmol) in MeOH (20 ml) under nitrogen wasadded 10% Pd/C (15 mg, 0.014 mmol). The mixture was charged with H₂ (50psi) and on Parr shaker for 3 days. The reaction mixture was filteredthrough Celite and the filtrate was concentrated in vacuo to give thecrude product. LC/MS m/z 314.25 (M+H)⁺, 1.67 min (Method 2).

Step 2: Preparation of a Mixture of tert-butyl4-(2-((8aS)-6-(4-(methoxycarbonyl)phenyl)-5,5,8a-trimethyl-1,2,3,5,6,7,8,8a-octahydroisoquinoline-2-carbonyl)phenyl)piperazine-1-carboxylateand tert-butyl4-(2-((8aS)-6-(4-(methoxycarbonyl)phenyl)-5,5,8a-trimethyl-1,2,3,4,4a,5,8,8a-octahydroisoquinoline-2-carbonyl)phenyl)piperazine-1-carboxylate

To a solution of crude mixture from step 1 (33 mg, 0.094 mmol) and2-(4-(tert-butoxycarbonyl)piperazin-1-yl)benzoic acid (43 mg, 0.14 mmol)in CH₂Cl₂ (5 ml) was added DIPEA (0.08 ml, 0.47 mmol) followed by HATU(54 mg, 0.14 mmol). The resulted solution was stirred at RT for 2 h. Thereaction mixture was diluted with CH₂Cl₂ (10 ml) and washed with H₂O(2×10 ml) followed by brine (10 ml), dried over Na₂SO₄, and concentratedin vacuo to give crude product without purification. LC/MS m/z 602.50(M+H)⁺, 2.63 min (Method 2).

Step 3: Preparation of a Mixture of4-((8aS)-2-(2-(4-(tert-butoxycarbonyl)piperazin-1-yl)benzoyl)-5,5,8a-trimethyl-1,2,3,5,6,7,8,8a-octahydroisoquinolin-6-yl)benzoicacid and4-((8aS)-2-(2-(4-(tert-butoxycarbonyl)piperazin-1-yl)benzoyl)-5,5,8a-trimethyl-1,2,3,4,4a,5,8,8a-octahydroisoquinolin-6-yl)benzoicacid

To a solution of crude mixture from step 2 in dioxane (2 ml) and MeOH (1ml) was added 1N NaOH (1 ml). The mixture was stirred at 50° C. for 4 h.The reaction mixture was purified by Prep HPLC to give the desiredproduct as a solid. LC/MS m/z 588.45 (M+H)⁺, 2.45 min (Method 2).

Step 4

To a solution of a mixture from step 3 in MeOH (10 ml) under nitrogenwas added 10% Pd/C (30 mg, 0.028 mmol). The mixture was charged with H2(50 psi) and on Parr shaker for 3 days. The reaction mixture wasfiltered through Celite and the filtrate was concentrated in vacuo. Thecrude product was purified by Prep HPLC to give the title compound as asolid. LC/MS m/z 590.45 (M+H)⁺, 2.48 min (Method 2).

The examples in Table 7 were prepared from intermediate 1 by theprocedure described in Examples 83 using the reagents indicated in thetable:

TABLE 7 Obs Ex Reagent MW (M + 1)⁺ RT Met 84 1-(tert-butoxycarbonyl)-4-588.36 589.36 4.39 7 phenylpiperidine-4-carboxylic acid 852-(1H-benzo[d]imidazol-2- 521.27 522.27 3.6  7 yl)benzoic acid 86Boc-D-Leu-OH 701.44 702.5  2.89 6 87 Boc-L-Leu-OH 701.44 702.5  2.88 688 Boc-D-Leu-OH and 5% Rhodium 699.42 700.45 2.94 6 on alumina ascatalyst 89 Boc-L-Leu-OH and 5% Rhodium 699.42 700.45 2.85 6 on aluminaas catalyst Ex = Example; MW = Molecular weight; Obs = Observed; RT =Retention time; Met = LC/MS Method.

Examples 90 and Example 91 Preparation of4-((6R,8aS)-2,5,5,8a-tetramethyldecahydroisoquinolin-6-yl)benzoic acidand 4-((6S,8aS)-2,5,5,8a-tetramethyldecahydroisoquinolin-6-yl)benzoicacid

Step 1: Preparation of methyl4-((8aS)-2,5,5,8a-tetramethyldecahydroisoquinolin-6-yl)benzoate

To a solution of methyl(S)-4-(5,5,8a-trimethyl-1,2,3,5,8,8a-hexahydroisoquinolin-6-yl)benzoatehydrochloride (50 mg, 0.144 mmol) in MeOH (20 ml) under nitrogen wasadded platinum(IV) oxide (29 mg, 0.13 mmol). The mixture was chargedwith H2 (50 psi) and on Parr shaker for 2 days. The reaction mixture wasfiltered through Celite and the filtrate was concentrated in vacuo togive the crude product. LC/MS m/z 330.20 (M+H)⁺, 1.56 min (Method 2).

Step 2

To a solution of crude methyl4-((8aS)-2,5,5,8a-tetramethyldecahydroisoquinolin-6-yl)benzoate indioxane (2 ml) and MeOH (1 ml) was added 1N NaOH (1 ml). The mixture wasstirred at 50° C. for 4 h. The crude mixture was purified by Prep HPLCto give the isomers respectively as solids.

Example 90: Isomer 1

¹H NMR (500 MHz, DMSO-d6) δ 7.83 (d, J=8.2 Hz, 2H), 7.31 (d, J=8.2 Hz,2H), 2.95-2.89 (m, 1H), 2.48 (dd, J=13.4, 2.1 Hz, 1H), 2.33 (d, J=9.8Hz, 1H), 2.27-2.17 (m, 1H), 2.11 (s, 3H), 1.83-1.76 (m, 1H), 1.56 (d,J=10.4 Hz, 1H), 1.54-1.48 (m, 2H), 1.44-1.37 (m, 2H), 1.27-1.18 (m, 1H),1.13 (s, 3H), 1.01-0.95 (m, 1H), 0.71 (s, 3H), 0.66 (s, 3H). LC/MS m/z316.30 (M+H)⁺, 1.78 min (Method 1).

Example 91: Isomer 2

¹H NMR (500 MHz, DMSO-d6) δ 7.79 (d, J=7.9 Hz, 2H), 7.28 (d, J=7.9 Hz,2H), 2.85-2.79 (m, 1H), 2.76-2.70 (m, 1H), 2.30-2.11 (m, 3H), 2.08 (s,3H), 1.84-1.73 (m, 1H), 1.68-1.60 (m, 2H), 1.59-1.52 (m, 1H), 1.45-1.37(m, 1H), 1.08 (s, 3H), 1.10-1.02 (m, 2H), 0.98 (s, 3H), 0.66 (s, 3H).LC/MS m/z 316.30 (M+H)⁺, 2.12 min (Method 1).

Example 92 Preparation of4-((S)-2-(1-((tert-butoxycarbonyl)-D-leucyl)-4-phenylpiperidine-4-carbonyl)-5,5,8a-trimethyl-1,2,3,5,8,8a-hexahydroisoquinolin-6-yl)benzoicacid

Step 1: Preparation of methyl4-((S)-2-(1-((tert-butoxycarbonyl)-D-leucyl)-4-phenylpiperidine-4-carbonyl)-5,5,8a-trimethyl-1,2,3,5,8,8a-hexahydroisoquinolin-6-yl)benzoate

To a solution of methyl(S)-4-(5,5,8a-trimethyl-2-(4-phenylpiperidine-4-carbonyl)-1,2,3,5,8,8a-hexahydroisoquinolin-6-yl)benzoatehydrochloride (100 mg, 0.187 mmol) and Boc-D-Leu-OH (86 mg, 0.374 mmol)in CH₂C12 (10 ml) was added DIPEA (0.33 ml, 1.87 mmol) followed by HATU(142 mg, 0.374 mmol). The resulted solution was stirred at RT overnight.The reaction mixture was concentrated in vacuo. The crude product waspurified by silica gel column eluted with 25% EtOAc/hexanes to give thedesired product (115 mg, 86%) as a solid. LC/MS m/z 712.40 (M+H)⁺, 2.92min (Method 2).

Step 2

To a solution of methyl4-((S)-2-(1-((tert-butoxycarbonyl)-D-leucyl)-4-phenylpiperidine-4-carbonyl)-5,5,8a-trimethyl-1,2,3,5,8,8a-hexahydroisoquinolin-6-yl)benzoate(46 mg, 0.065 mmol) in dioxane (2 ml) and MeOH (1 ml) was added 1N NaOH(1 ml). The mixture was stirred at 50° C. for 4 h. The reaction mixturewas purified by Prep HPLC to give the desired product (29 mg, 64%) as asolid. LC/MS m/z 698.45 (M+H)⁺, 2.72 min (Method 2).

The examples in Table 8 were prepared from intermediate 2 by theprocedure described in Example 92 using the reagents indicated in thetable:

TABLE 8 Obs Ex Reagent MW (M + 1)⁺ RT Met 93 Boc-L-Leu-OH 697.4 698.452.76  6 94 2-(1,1- 659.3 660.35 2.244 6 dioxidothiomorpholino)aceticacid 95 3-(1,1- 673.3 674.35 2.171 6 dioxidothiomorpholino)propanoicacid Ex = Example; MW = Molecular weight; Obs = Observed; RT = Retentiontime; Met = LC/MS Method.

Example 96 Preparation of(S)-4-(2-(1-(2-(1,1-dioxidothiomorpholino)ethyl)-4-phenylpiperidine-4-carbonyl)-5,5,8a-trimethyl-1,2,3,5,8,8a-hexahydroisoquinolin-6-yl)benzoicacid

Step 1: Preparation of methyl(S)-4-(2-(1-(2-(1,1-dioxidothiomorpholino)ethyl)-4-phenylpiperidine-4-carbonyl)-5,5,8a-trimethyl-1,2,3,5,8,8a-hexahydroisoquinolin-6-yl)benzoate

A suspension of methyl(S)-4-(5,5,8a-trimethyl-2-(4-phenylpiperidine-4-carbonyl)-1,2,3,5,8,8a-hexahydroisoquinolin-6-yl)benzoatehydrochloride (25 mg, 0.047 mmol), 4-(2-chloroethyl)thiomorpholine1,1-dioxide (55 mg, 0.28 mmol), K3PO4 (80 mg, 0.38 mmol) and NaI (28 mg,0.19 mmol) in MeCN (3 ml) was heated at 100° C. overnight. The reactionmixture was diluted with CH₂Cl₂ (10 ml), washed with H₂O (10 ml), driedover Na₂SO₄ and concentrated in vacuo to give the crude product withoutpurification.

LC/MS m/z 660.40 (M+H)⁺, 2.22 min (Method 2).

Step 2

To a solution of crude methyl(S)-4-(2-(1-(2-(1,1-dioxidothiomorpholino)ethyl)-4-phenylpiperidine-4-carbonyl)-5,5,8a-trimethyl-1,2,3,5,8,8a-hexahydroisoquinolin-6-yl)benzoateindioxane (2 ml) and MeOH (1 ml) was added 1N NaOH (1 ml). The mixture wasstirred at 50° C. for 4 h. The reaction mixture was purified by PrepHPLC to give the desired product (16 mg, 54%) as a solid. LC/MS m/z646.40 (M+H)⁺, 2.05 min (Method 2).

Example 97 Preparation of(S)-4-(2-(2-(5,6-dimethyl-1H-benzo[d]imidazol-2-yl)benzoyl)-5,5,8a-trimethyl-1,2,3,5,8,8a-hexahydroisoquinolin-6-yl)benzoicacid

Step 1: Preparation of 2-(5,6-dimethyl-1H-benzo[d]imidazol-2-yl)benzoicacid

To a solution of 2-formylbenzoic acid (500 mg, 3.33 mmol) and4,5-dimethylbenzene-1,2-diamine (454 mg, 3.33 mmol) in DMF (50 ml) wasadded sodium metabisulfite (696 mg, 3.66 mmol). The mixture was stirredat 60° C. overnight. The mixture was concentrated in vacuo. The residuewas partitioned between EtOAc (20 ml) and 1N NaOH (20 ml). The separatedaqueous layer was neutralized with 1N HCl to pH˜7. The precipitatedsolid was collected by filtration, washed with H₂O, and dried to givethe desired product (886 mg, 100%). ¹H NMR (400 MHz, DMSO-d6) δ 8.09 (d,J=6.5 Hz, 1H), 7.77 (dd, J=7.7, 1.1 Hz, 1H), 7.54-7.47 (m, 1H),7.47-7.42 (m, 1H), 7.34 (s, 2H), 2.32 (s, 6H). LC/MS m/z 267.10 (M+H)⁺,1.80 min (Method 9).

Step 2: Preparation of 2-(5,6-dimethyl-1H-benzo[d]imidazol-2-yl)benzoylchloride

To a suspension of 2-(5,6-dimethyl-1H-benzo[d]imidazol-2-yl)benzoic acid(85 mg, 0.32 mmol) in CH₂Cl₂ (5 ml) was added oxalyl chloride (2 M inCH₂Cl₂) (0.24 ml, 0.48 mmol). The reaction mixture was stirred at RT for2 h and concentrated in vacuo to give the crude product as solid.

Step 3: Preparation of methyl(S)-4-(2-(2-(5,6-dimethyl-1H-benzo[d]imidazol-2-yl)benzoyl)-5,5,8a-trimethyl-1,2,3,5,8,8a-hexahydroisoquinolin-6-yl)benzoate

To a solution of methyl(S)-4-(5,5,8a-trimethyl-1,2,3,5,8,8a-hexahydroisoquinolin-6-yl)benzoatehydrochloride (111 mg, 0.32 mmol) and crude2-(5,6-dimethyl-1H-benzo[d]imidazol-2-yl)benzoyl chloride in CH₂Cl₂ (5ml) was added TEA (0.07 ml, 0.48 mmol). The reaction mixture was stirredat RT overnight. The reaction mixture was concentrated in vacuo. Thecrude product was purified by silica gel column eluted with 35%EtOAc/hexanes to give the desired product (66 mg, 89%) as a solid. LC/MSm/z 560.35 (M+H)⁺, 2.37 min (Method 2).

Step 4

To a solution of methyl(S)-4-(2-(2-(5,6-dimethyl-1H-benzo[d]imidazol-2-yl)benzoyl)-5,5,8a-trimethyl-1,2,3,5,8,8a-hexahydroisoquinolin-6-yl)benzoate(26 mg, 0.05 mmol) in dioxane (2 ml) and MeOH (1 ml) was added 1N NaOH(1 ml). The mixture was stirred at 50° C. for 4 h. The crude product waspurified by Prep HPLC to give the desired product (19 mg, 75%) as asolid. LC/MS m/z 546.30 (M+H)⁺, 2.19 min (Method 2).

The example in Table 9 was prepared by the procedure described inExample 97 using the starting material indicated in the table instead of4,5-dimethylbenzene-1,2-diamine

TABLE 9 Obs Ex Reagent MW (M + 1)⁺ RT Met 983,4-dimethylbenzene-1,2-diamine 545.3 546.3 2.27 6 Ex = Example; MW =Molecular weight; Obs = Observed; RT = Retention time; Met = LC/MSMethod.

Example 99 Preparation of(S)-4-(2-(2-(5,6-dibromo-1H-benzo[d]imidazol-2-yl)benzoyl)-5,5,8a-trimethyl-1,2,3,5,8,8a-hexahydroisoquinolin-6-yl)benzoicacid

Step 1: Preparation of methyl(S)-4-(2-(2-(5,6-dibromo-1H-benzo[d]imidazol-2-yl)benzoyl)-5,5,8a-trimethyl-1,2,3,5,8,8a-hexahydroisoquinolin-6-yl)benzoate

To a solution of methyl(S)-4-(2-(2-formylbenzoyl)-5,5,8a-trimethyl-1,2,3,5,8,8a-hexahydroisoquinolin-6-yl)benzoate(50 mg, 0.113 mmol) and 4,5-dibromobenzene-1,2-diamine (30 mg, 0.113mmol) in DMF (2 ml) was added sodium metabisulfite (24 mg, 0.124 mmol).The mixture was stirred at 60° C. overnight. The mixture wasconcentrated in vacuo. The residue was partitioned between EtOAc (20 ml)and H₂O (20 ml). The separated aqueous layer was extracted with EtOAc(20 ml). The combined organic layers were washed brine (20 ml), driedover Na₂SO₄, and concentrated in vacuo. The crude product was purifiedby silica gel column eluted with 35% EtOAc/hexanes to give the desiredproduct (62 mg, 80%) as a solid. LC/MS m/z 688.10 (M+H)⁺, 2.91 min(Method 2).

Step 2

To a solution of methyl(S)-4-(2-(2-(5,6-dibromo-1H-benzo[d]imidazol-2-yl)benzoyl)-5,5,8a-trimethyl-1,2,3,5,8,8a-hexahydroisoquinolin-6-yl)benzoate(53 mg, 0.077 mmol) in 1,4-dioxane (2 ml) and MeOH (1 ml) was added 1NNaOH (1 ml). The mixture was stirred at 50° C. for 2 h. The crudeproduct was purified by Prep HPLC to give the desired product (43 mg,81%) as a solid. LC/MS m/z 674.10 (M+H)⁺, 2.73 min (Method 2).

The examples in Table 10 were prepared from intermediate 3 by theprocedure described in Example 99 using the reagents indicated in thetable instead of 4,5-dibromobenzene-1,2-diamine:

TABLE 10 Obs Ex Reagent MW (M + 1)⁺ RT Met 1002-methyl-4-phenyl-1,2,3,4- 662.3 663.4 2.38 6tetrahydroisoquinoline-7,8- diamine 101 2-methyl-4-phenyl-1,2,3,4- 662.3663.4 2.49 6 tetrahydroisoquinoline-7,8- diamine Ex = Example; MW =Molecular weight; Obs = Observed; RT = Retention time; Met = LC/MSMethod.Section 2LCMS Methods:Method-A:Column: Waters BEH C18, 2.0×50 mm, 1.7-μm particlesMobile Phase A: 5:95 acetonitrile:water with 10 mM ammonium acetateMobile Phase B: 95:5 acetonitrile:water with 10 mM ammonium acetateTemperature: 40° C.Gradient: 0.5 min hold at 0% B, 0-100% B over 4 minutes, then a0.5-minute hold at 100% BFlow: 1 mL/minMethod-M:Column: Waters BEH C18, 2.0×50 min, 1.7-μm particlesMobile Phase A: 5:95 methanol:water with 10 mM ammonium acetateMobile Phase B: 95:5 methanol:water with 10 mM ammonium acetateTemperature: 40° C.Gradient: 0.5 min hold at 0% B, 0-100% B over 4 minutes, then a0.5-minute hold at 100% BFlow: 0.5 mL/min.

Examples A1-A126 were prepared from intermediate 1 and commerciallyavailable carboxylic acids by the following general method:

Prepared a solution of HATU (684 mg, 1.8 mmol) in DMF (12.0 mL). To eachof the carboxylic acids weighed into 16×48 mm threaded vials was added0.5 mL of the HATU solution. The reactions were agitated at 350 rpm onan Innova platform shaker at room temperature for 10 minutes. Prepared asolution of the (S)-methyl4-(5,5,8a-trimethyl-1,2,3,5,8,8a-hexahydroisoquinolin-6-yl)benzoate (417mg, 1.2 mmol) and DIPEA (840 μL, 4.8 mmol). Added 0.5 mL of the(S)-methyl4-(5,5,8a-trimethyl-1,2,3,5,8,8a-hexahydroisoquinolin-6-yl)benzoate/DIPEAsolution to each of the reaction vials. Capped vials and agitated at 350rpm on an Innova platform shaker at room temperature for 18 hrs. Sampleswere blown down in the Zymark tabletop dryer at 35° C. for 3 hours.Prepared a solution of lithium hydroxide Monohydrate (403 mg, 9.6 mmol)in water (4.8 mL). To each of the reaction vials was added 0.8 mLdioxane and 0.2 mL of the lithium hydroxide solution. Capped vials andagitated at 350 rpm on an Innova platform shaker at 70° C. for 18 hrs.Samples were blown down in the Zymark tabletop dryer at 35° C. for 3hours. Added 1.0 mL DMF to each vial. Transferred contents to a 96 well2 mL filter plate, collecting into a 96 well deepwell plate. Rinsedreaction vials w/500 DMF each and transferred rinses to the appropriatewells of the filter plate. Transferred contents to 16×48 mm threadedvials, followed by automated HPLC purification and LCMS analyses. SeeTable 11.

TABLE 11 Obs Ex Structure MW Ion RT Met A1

487.61 488.3 2.66 A A2

458.57 459.1 2.55 A A3

503.59 502.3 2.34 A A4

503.59 504.2 3.83 M A5

441.56 440.3 3.84 M A6

476.01 476.2 4.00 M A7

379.49 380.2 2.08 A A8

490.03 490.3 2.75 A A9

469.61 470.3 2.77 A A10

504.06 504.3 2.94 A A11

499.64 500.3 2.71 A A12

493.59 494.3 3.93 M A13

493.59 494.3 2.58 A A14

505.60 506.3 3.75 M A15

493.59 494.3 4.05 M A16

505.60 506.3 3.78 M A17

474.98 475.3 4.07 M A18

470.56 471.2 3.73 M A19

505.60 506.3 3.76 M A20

498.61 499.2 2.12 M A21

528.64 527.3 2.64 A A22

452.54 453.2 3.60 M A23

452.54 453.2 3.43 M A24

521.60 522.3 3.07 M A25

511.61 510.4 3.46 M A26

479.59 480.3 2.99 M A27

471.59 472.3 2.32 A A28

518.09 518.4 3.17 A A29

452.54 453.3 3.42 M A30

503.59 504.3 3.77 M A31

511.61 512.3 1.74 A A32

517.58 518.3 2.95 M A33

498.57 499.3 3.11 M A34

483.64 484.3 4.41 M A35

483.64 484.3 4.39 M A36

583.77 584.4 4.54 M A37

508.63 509.3 3.37 M A38

452.54 453.3 3.34 M A39

457.58 458.3 3.92 M A40

482.58 483.3 4.16 M A41

492.99 493.2 2.52 M A42

484.61 485.3 3.63 M A43

497.67 498.3 3.18 A A44

455.59 456.3 4.02 M A45

468.54 469.3 2.06 A A46

485.58 486.3 2.57 A A47

499.62 500.3 2.09 A A48

484.59 485.3 2.02 A A49

515.60 517.3 1.94 A A50

495.57 496.3 2.07 A A51

495.61 496.3 1.94 A A52

493.02 493.3 2.21 A A53

442.51 443.3 2.76 M A54

528.66 529.3 2.27 A A55

498.64 499.3 2.17 A A56

493.60 494.3 1.98 A A57

495.61 496.4 1.95 A A58

467.57 468.3 1.93 A A59

441.52 442.3 1.71 A A60

525.64 526.4 3.69 M A61

431.53 432.3 1.80 A A62

524.61 525.3 1.84 A A63

495.58 496.3 2.39 A A64

481.59 482.3 2.19 A A65

497.58 498.3 2.17 A A66

441.53 442.3 2.08 A A67

434.57 435.3 1.37 A A68

577.75 578.4 1.87 A A69

515.04 515.3 3.74 M A70

500.56 499.4 2.20 A A71

502.61 503.4 2.23 A A72

455.55 456.3 2.02 A A73

445.55 446.3 1.85 A A74

586.72 587.4 2.27 A A75

497.58 498.3 3.56 M A76

501.55 502.3 3.77 M A77

509.64 510.4 2.04 A A78

483.62 484.3 2.55 A A79

516.04 516.3 2.15 A A80

526.65 527.3 3.78 M A81

481.59 482.4 2.03 A A82

470.56 471.3 1.78 A A83

534.67 535.3 3.54 M A84

496.64 497.4 3.49 M A85

508.65 509.4 2.24 A A86

417.55 418.3 2.28 A A87

521.65 522.4 3.80 M A88

496.60 497.4 2.28 A A89

472.60 473.3 2.26 A A90

481.58 482.3 3.90 M A91

517.63 518.4 3.48 M A92

494.62 495.4 2.34 A A93

471.55 472.3 1.67 A A94

467.56 468.3 2.11 A A95

496.64 497.3 1.71 A A96

521.00 521.3 2.18 A A97

506.59 507.3 2.03 A A98

513.65 514.3 3.68 M A99

492.57 493.4 2.82 M A100

417.50 418.3 1.70 A A101

459.62 460.4 2.71 A A102

473.65 474.4 2.76 A A103

499.60 500.4 2.63 A A104

468.55 469.3 2.01 A A105

453.53 454.3 1.70 A A106

467.56 468.3 1.67 A A107

469.57 470.24 1.85 A A108

470.56 471.3 1.88 A A109

472.60 473.3 2.01 A A110

511.61 512.4 3.34 M A111

487.61 488.4 2.67 A A112

516.64 517.4 2.60 A A113

483.62 484.3 2.46 A A114

517.63 518.4 2.00 A A115

487.61 488.3 2.68 A A116

561.11 559.4 3.82 M A117

448.60 449.3 2.52 M A118

508.61 509.4 3.14 M A119

529.63 530.3 3.48 M A120

522.05 522.3 4.05 M A121

485.60 486.3 3.25 M A122

529.63 530.4 3.56 M A123

534.67 535.4 2.71 A A124

516.63 517.5 2.64 A A125

581.06 579.5 2.55 A A126

546.61 547.4 2.22 A

Examples A127-A253 were prepared from intermediate 2 and commerciallyavailable carboxylic acids by the following general method:

Prepared a solution of HATU (821 mg, 2.16 mmol) in DMF (24 mL). To eachof the 48 carboxylic acids weighed into 16×48 mm threaded vials wasadded 0.5 mL of the HATU solution. The reactions were agitated at 350rpm on an Innova platform shaker at room temperature for 10 minutes.Prepared a solution of the (S)-methyl4-(5,5,8a-trimethyl-2-(4-phenylpiperidine-4-carbonyl)1,2,3,5,8,8a-hexahydroisoquinolin-6-yl)benzoate(720 mg, 1.44 mmol) and DIPEA (1.0 mL, 5.8 mmol) in DMF (24 mL). Added0.5 mL of the (S)-methyl4-(5,5,8a-trimethyl-2-(4-phenylpiperidine-4-carbonyl)1,2,3,5,8,8a-hexahydroisoquinolin-6-yl)benzoate/DIPEAsolution to each of the reaction vials. Capped vials and agitated at 350rpm on an Innova platform shaker at room temperature for 18 hrs. Sampleswere blown down in the Zymark tabletop dryer at 35° C. for 3 hours.Prepared a solution of Lithium Hydroxide Monohydrate (483 mg, 11.5 mmol)in water (9.6 mL). To each of the reaction vials was added 0.8 mLdioxane and 0.2 mL of the lithium hydroxide solution. Capped vials andagitated at 350 rpm on an Innova platform shaker at 70° C. for 18 hrs.Added 100 μL glacial acetic acid to each vial. Samples were blown downin the Zymark tabletop dryer at 35° C. for 3 hours. Added 1.0 mL DMF toeach vial. Transferred contents to a 96 well 2-mL filter plate,collecting into a 96 well deepwell plate. Rinsed reaction vials w/500 μLDMF each and transferred rinses to the appropriate wells of the filterplate. Transferred contents to 16×48 mm threaded vials. Submitted forHPLC purification, and LCMS analyses, results are shown in thespreadsheet. See Table 12.

TABLE 12 Obs Ex Structure MW Ion RT Met A127

592.75 593.3 1.78 A A128

625.80 626.5 2.11 A A129

569.73 570.5 3.49 M A130

597.79 598.5 1.98 A A131

611.77 612.5 2.17 A A132

552.70 553.5 3.85 M A133

611.77 612.5 3.55 M A134

586.78 587.5 3.96 M A135

637.81 638.5 2.16 A A136

596.76 595.5 3.71 M A137

597.74 598.4 2.03 A A138

685.85 686.6 3.93 M A139

622.72 623.5 4.09 M A140

598.73 599.5 3.41 M A141

600.74 601.5 3.64 M A142

580.76 581.5 4.09 M A143

604.76 605.5 3.45 M A144

697.86 698.7 3.82 M A145

697.90 698.7 4.30 M A146

584.75 585.5 2.35 A A147

625.80 626.5 3.78 M A148

597.74 598.4 2.17 A A149

671.82 672.6 3.85 M A150

623.78 624.5 3.58 M A151

595.73 596.5 2.04 A A152

747.94 748.7 3.83 M A153

625.80 626.6 3.80 M A154

639.82 640.5 2.40 A A155

578.74 579.5 2.57 A A156

715.94 716.6 4.20 M A157

698.85 699.6 3.80 M A158

695.89 696.6 4.11 M A159

667.83 666.8 3.89 M A160

636.82 635.5 3.96 M A161

658.05 657.3 2.90 A A162

655.89 656.6 4.16 M A163

697.90 698.6 3.03 A A164

667.83 668.6 2.67 A A165

764.99 765.8 2.50 A A166

701.91 702.5 3.81 M A167

723.94 724.6 4.29 M A168

723.95 724.7 2.96 A A169

681.86 682.6 2.69 A A170

709.91 710.6 4.28 M A171

725.91 726.6 2.34 A A172

711.89 712.6 3.83 M A173

624.81 625.5 2.00 A A174

610.78 611.5 3.97 M A175

651.83 652.6 2.43 A A176

623.82 624.5 3.47 M A177

639.82 640.6 2.14 A A178

609.80 610.5 2.13 M A179

595.73 596.5 3.43 M A180

595.77 596.5 3.43 M A181

609.80 610.5 3.45 M A182

711.93 712.6 4.43 M A183

697.90 698.6 3.02 A A184

697.90 698.6 4.30 M A185

741.97 742.7 4.34 M A186

685.85 686.6 4.00 M A187

695.89 696.6 2.81 A A188

681.86 682.6 2.73 A A189

635.62 635.4 4.18 M A190

552.70 553.5 3.85 M A191

570.72 569.6 3.77 M A192

542.67 543.4 3.49 M A193

632.76 633.5 2.79 A A194

566.73 567.5 2.55 A A195

590.78 591.5 2.58 A A196

590.77 591.4 3.86 M A197

625.23 625.4 3.90 M A198

604.80 605.4 3.99 M A199

562.72 563.4 3.63 M A200

576.75 577.4 3.73 M A201

640.81 641.4 3.61 M A202

591.76 592.4 3.81 M A203

696.87 697.6 2.46 A A204

699.91 700.6 2.72 A A205

609.80 610.5 3.59 M A206

710.90 711.5 4.05 M A207

611.73 612.3 3.32 M A208

603.19 603.3 3.95 M A209

625.75 626.5 3.49 M A210

622.84 623.5 3.13 A A211

582.77 583.5 2.78 A A212

623.82 624.5 3.53 M A213

582.73 583.5 2.31 A A214

597.74 598.5 3.55 M A215

711.93 712.6 3.19 A A216

570.72 571.5 2.27 A A217

611.77 612.5 2.17 A A218

597.79 598.5 2.03 A A219

697.92 698.6 3.03 A A220

624.81 625.5 2.76 A A221

624.81 625.5 2.57 A A222

596.76 597.5 2.41 A A223

741.96 742.6 3.08 A A223

685.85 686.6 2.62 A A224

695.89 696.6 2.81 A A225

610.78 611.5 2.35 A A226

681.86 682.6 2.73 A A227

638.84 639.5 2.04 A A228

669.85 670.5 2.65 A A229

623.78 624.5 2.17 A A230

596.76 597.4 3.70 M A231

711.93 712.6 3.20 A A232

582.73 583.4 2.31 A A233

680.83 681.5 2.59 A A234

592.77 593.5 2.60 A A235

582.73 583.4 3.73 M A236

675.83 676.5 2.07 A A237

609.80 610.5 3.58 M A238

597.79 598.5 2.09 A A239

583.76 584.5 3.39 M A240

611.77 612.5 2.37 A A241

673.86 674.5 2.20 A A242

624.81 625.5 2.48 A A243

709.91 710.6 4.18 M A244

654.80 655.5 3.39 M A245

609.80 610.5 2.14 A A246

595.77 596.4 3.45 M A247

583.72 584.3 3.30 M A248

655.82 656.5 4.00 M A249

655.82 656.5 3.98 M A250

697.90 698.5 4.28 M A251

697.90 698.6 4.29 M A252

655.82 656.5 4.00 M A253

683.88 684.5 4.19 M

Examples A254-A338 were prepared from intermediate 3 and commerciallyavailable diamines by the following general method:

Prepared a solution of (S)-methyl4-(2-(2-formylbenzoyl)-5,5,8a-trimethyl-1,2,3,5,8,8a-hexahydroisoquinolin-6-yl)benzoate(190 mg, 432 μmol) in NMP (6.0 mL). To each of the 16×48 mm threadedvials containing the diamines was added 0.5 mL of the (S)-methyl4-(2-(2-formylbenzoyl)-5,5,8a-trimethyl-1,2,3,5,8,8a-hexahydroisoquinolin-6-yl)benzoatesolution followed by the sodium metabisulfite (7.4 mg). Added a stir barto each vial, capped and allowed to stir at room temp for 10 minutesbefore heating to 110° C. w/stirring for 18 hrs. Samples were blown downin the Zymark tabletop dryer at 40° C. for 3 hrs. Prepared a solution ofLithium Hydroxide (143.4 mg, 3.4 mmol) in water (2.4 mL). To each of thereaction vials was added 800 μL Dioxane and 200 μL Lithium Hydroxidesolution. Capped vial and heated to 70° C. w/stirring. After 5 hrs,reaction mixtures were blown down in the Zymark tabletop dryer at 40° C.for 2 hrs. Added 1.0 mL DMF to each vial. Vortexed to dissolve.Transferred contents to empty SPE cartridges for filtration, collectinginto 16×48 mm round bottom vials. Rinsed reaction vials w/500 μL DMFeach, and transferred rinses to the corresponding SPE cartridges.Submitted for HPLC purification, and LCMS analyses, results are shown inthe spreadsheet. See Table 13.

TABLE 13 Obs Ex Structure MW Ion RT Met A254

566.10 566.3 4.00 M A255

531.64 532.3 3.77 M A256

531.64 532.3 3.80 M A257

552.06 550.3 2.52 A A258

535.61 534.3 2.33 A A259

585.62 586.3 2.60 A A260

570.06 570.2 3.93 M A261

547.64 548.4 2.24 A A262

553.60 553.9 2.43 A A263

589.68 590.2 3.79 M A264

553.60 554.3 3.80 M A265

586.52 586.2 4.04 M A266

535.62 536.3 2.22 A A267

553.61 554.2 2.24 A A268

586.52 584.1 4.13 M A269

542.63 543.2 2.09 A A270

552.07 552.2 2.33 A A271

566.10 566.3 3.98 M A272

562.63 563.2 2.30 A A273

562.63 563.2 3.64 M A274

531.65 532.3 2.17 A A275

640.83 641.7 3.25 M A276

566.09 566.5 3.83 M A277

690.67 690.3 4.28 M A278

677.81 678.4 3.72 M A279

593.73 594.3 2.67 A A280

690.89 691.5 2.58 A A281

621.74 622.6 3.83 M A282

620.06 620.6 2.87 A A283

728.81 729.7 4.02 M A284

570.68 571.6 3.61 M A285

573.68 574.6 3.45 M A286

623.77 624.3 2.07 A A287

584.71 585.6 2.55 A A288

603.71 604.3 1.87 A A289

660.80 661.4 3.79 M A290

651.76 652.3 2.07 A A291

652.74 653.3 3.11 M A292

645.74 646.3 1.87 A A293

652.75 653.3 3.01 M A294

646.74 647.3 1.59 A A295

603.71 604.6 2.23 A A296

619.72 620.3 3.04 M A297

617.73 618.6 2.27 A A298

561.64 562.3 2.11 A A299

577.68 578.3 2.20 A A300

675.74 676.1 3.31 A A301

627.75 628.2 2.32 A A302

637.77 638.1 3.11 M A303

597.61 598.3 2.46 A A304

624.57 624.3 2.59 A A305

573.64 574.3 3.20 M A306

567.68 568.3 3.88 M A307

567.68 568.3 2.41 A A308

592.64 593.3 2.29 A A309

532.64 533.3 4.13 M A310

597.50 597.4 2.74 A A311

548.64 549.4 2.55 A A312

572.69 573.5 4.39 M A313

546.66 547.4 2.82 A A314

554.59 555.3 4.10 M A315

597.51 597.3 2.80 A A316

536.60 537.4 2.61 A A317

644.50 645.3 4.17 M A318

553.06 553.3 2.78 A A319

627.52 627.1 4.19 M A320

548.64 549.4 3.92 M A321

597.50 597.1 4.12 M A322

536.59 537.3 3.92 M A323

601.52 601.3 4.53 M A324

568.66 569.4 4.26 M A325

518.61 519.3 3.92 M A326

532.64 533.4 4.06 M A327

586.60 587.3 2.85 A A328

562.65 563.4 2.79 A A329

602.60 603.3 4.19 M A330

546.66 547.2 4.16 M A331

532.63 533.2 4.01 M A332

553.06 553.3 2.79 A A333

532.63 533.4 4.13 M A334

548.64 549.4 3.92 M A335

536.59 537.4 3.96 M A336

574.71 575.5 4.38 M A337

594.70 595.5 3.04 A A338

554.59 555.3 2.68 ASection 3LCMS MethodsMethod BStart % B=0, Final % B=100Gradient Time=2 minFlow Rate=1.0 mL/minWavelength=220Solvent A=10% MeOH-90% H₂O-0.1% TFASolvent B=90% MeOH-10% H₂O-0.1% TFAColumn=PHENOMENEX-LUNA 2.0×30 mm 3 umMethod CStart % B=0Final % B=100Gradient Time=4 minFlow Rate=0.8 mL/minWavelength=220Solvent A=10% MeOH-90% H₂O-0.1% TFASolvent B=90% MeOH-10% H₂O-0.1% TFAColumn=Xbridge Phenyl 2.1×50 mm 2.5 umMethod DStart % B=0, Final % B=100Gradient Time=2 minFlow Rate=1.0 mL/minWavelength=220Solvent A=5% MeOH: 95% Water: 10 mM Ammonium ActetateSolvent B=95% MeOH: 5% Water: 10 mM Ammonium ActetateColumn=PHENOMENEX-LUNA C18, 2.0×30 mm 3 um

Preparation of Compounds Examples B1 and B2 Preparation of Compound B1(S)-4-(2-(3-(2-(2-(1,1-dioxidothiomorpholino)ethyl)-2H-tetrazol-5-yl)-5-nitrophenyl)-5,5,8a-trimethyl-1,2,3,5,8,8a-hexahydroisoquinolin-6-yl)benzoicacid and Compound B2(S)-4-(2-(3-(1-(2-(1,1-dioxidothiomorpholino)ethyl)-1H-tetrazol-5-yl)-5-nitrophenyl)-5,5,8a-trimethyl-1,2,3,5,8,8a-hexahydroisoquinolin-6-yl)benzoicacid

Step 1: Preparation of (S)-methyl4-(2-(3-cyano-5-nitrophenyl)-5,5,8a-trimethyl-1,2,3,5,8,8a-hexahydroisoquinolin-6-yl)benzoate

To a mixture of(S)-6-(4-(methoxycarbonyl)phenyl)-5,5,8a-trimethyl-1,2,3,5,8,8a-hexahydroisoquinolin-2-iumchloride (119 mg, 0.342 mmol) and 3-fluoro-5-nitrobenzonitrile (398 mg,2.395 mmol) in the presence of anhydrous potassium carbonate (284 mg,2.052 mmol) in a resealable pressure tube was added DMF (4 mL), followedby flushing with nitrogen. The tube was sealed, placed in an oil bath at125° C. for overnight. The resulted mixture was diluted with 50 mL ofethyl acetate and washed twice with water (2×20 mL). The organic layerswere collected and evaporated to yield a solid which was purified byflash chromatography. The fractions containing desired the product werecollected and dried under reduced pressure to give 65 mg of the titlecompound (41.5%) as a solid. LC/MS m/z 458.29 (M+H)⁺, 2.74 min (MethodB). ¹H NMR (400 MHz, CHLOROFORM-d) δ 8.03-7.94 (m, 2H), 7.86 (t, J=2.3Hz, 1H), 7.81-7.77 (m, 1H), 7.33 (dd, J=2.6, 1.1 Hz, 1H), 7.29-7.24 (m,2H), 5.76 (t, J=3.4 Hz, 1H), 5.64 (dd, J=6.0, 3.0 Hz, 1H), 4.11-4.04 (m,1H), 3.94 (s, 3H), 3.80 (dd, J=16.6, 2.8 Hz, 1H), 3.63 (d, J=12.0 Hz,1H), 2.99 (d, J=12.0 Hz, 1H), 2.18-2.12 (m, 2H), 1.35 (s, 3H), 1.30-1.26(m, 3H), 1.17 (s, 3H).

Step 2: Preparation of (S)-methyl4-(5,5,8a-trimethyl-2-(3-nitro-5-(1H-tetrazol-5-yl)phenyl)-1,2,3,5,8,8a-hexahydroisoquinolin-6-yl)benzoate

To a resealable tube was added (S)-methyl4-(2-(3-cyano-5-nitrophenyl)-5,5,8a-trimethyl-1,2,3,5,8,8a-hexahydroisoquinolin-6-yl)benzoate(50 mg, 0.109 mmol) and azidotributylstannane (0.079 mL, 0.287 mmol) intoluene (1 mL) under nitrogen. The pressure tube was sealed and warmedto 130° C. overnight. The crude reaction mixture was evaporated, washedwith water and extracted with ethyl acetate (2×10 mL). The organiclayers were combined and evaporated to dryness. The resulted solid waspurified by flash chromatography. The fractions containing the desiredproduct were collected and dried under reduced pressure to give 50 mg ofthe title compound (91%) as a solid. LC/MS m/z 501.26 (M+H)⁺, 2.52 min(method B).

Step 3: Preparation of (S)-methyl4-(2-(3-(1-(2-(1,1-dioxidothiomorpholino)ethyl)-1H-tetrazol-5-yl)-5-nitrophenyl)-5,5,8a-trimethyl-1,2,3,5,8,8a-hexahydroisoquinolin-6-yl)benzoateand (S)-methyl4-(2-(3-(2-(2-(1,1-dioxidothiomorpholino)ethyl)-2H-tetrazol-5-yl)-5-nitrophenyl)-5,5,8a-trimethyl-1,2,3,5,8,8a-hexahydroisoquinolin-6-yl)benzoate

A mixture of (S)-methyl4-(5,5,8a-trimethyl-2-(3-nitro-5-(1H-tetrazol-5-yl)phenyl)-1,2,3,5,8,8a-hexahydroisoquinolin-6-yl)benzoate(50 mg, 0.100 mmol), 4-(2-chloroethyl)thiomorpholine 1,1-dioxidehydrochloride (94 mg, 0.400 mmol), potassium phosphate (93 mg, 0.440mmol) and NaI (44.8 mg, 0.270 mmol) in Acetonitrile (5 mL) was heated upat 120° C. for 19 hours in a seal tube. The resulted mixture was dilutedwith 20 ml of ethyl acetate and washed with water. The organic layer wascollected and evaporated to dryness under reduced pressure, used in nextstep without further purification. LCMS showed two peaks with the samemolecular weight as the desired products. LC/MS m/z 662.4 (M+H)⁺, 2.39min, 2.59 min (method B).

Step 4

To a solution of (S)-methyl4-(2-(3-(1-(2-(1,1-dioxidothiomorpholino)ethyl)-1H-tetrazol-5-yl)-5-nitrophenyl)-5,5,8a-trimethyl-1,2,3,5,8,8a-hexahydroisoquinolin-6-yl)benzoateand(S)-4-(2-(3-(2-(2-(1,1-dioxidothiomorpholino)ethyl)-2H-tetrazol-5-yl)-5-nitrophenyl)-5,5,8a-trimethyl-1,2,3,5,8,8a-hexahydroisoquinolin-6-yl)benzoate(total 66.1 mg, 0.1 mmole) in dioxane (1.0 mL), THF (1.0 mL), MeOH (1.0mL) was added sodium hydroxide (1.0 mL). A yellow solution was formed.The mixture was stirred at 70° C. for 3 hours. The resulted solution waspurified by prep. HPLC. Two fractions with molecular weight of thedesired product but different retention times were collected separatelyand evaporated to dryness to giveS)-4-(2-(3-(1-(2-(1,1-dioxidothiomorpholino)ethyl)-1H-tetrazol-5-yl)-5-nitrophenyl)-5,5,8a-trimethyl-1,2,3,5,8,8a-hexahydroisoquinolin-6-yl)benzoicacid (3 mg, 4.2%) and(S)-4-(2-(3-(2-(2-(1,1-dioxidothiomorpholino)ethyl)-2H-tetrazol-5-yl)-5-nitrophenyl)-5,5,8a-trimethyl-1,2,3,5,8,8a-hexahydroisoquinolin-6-yl)benzoicacid (20 mg, 29.0%). LC/MS m/z 648.4 (M+H)⁺, 2.06 min (method B). ¹H NMR(400 MHz, CHLOROFORM-d) δ 8.07 (d, J=8.3 Hz, 2H), 7.89 (t, J=2.1 Hz,1H), 7.81 (s, 1H), 7.60 (s, 1H), 7.32 (d, J=8.3 Hz, 2H), 5.78 (t, J=3.3Hz, 1H), 5.65 (dd, J=6.0, 2.8 Hz, 1H), 4.64 (t, J=5.9 Hz, 2H), 4.17 (dd,J=16.8, 4.0 Hz, 1H), 3.89-3.82 (m, 1H), 3.75-3.70 (m, 1H), 3.22 (d,J=6.0 Hz, 2H), 3.04 (d, J=6.0 Hz, 5H), 2.98-2.93 (m, 4H), 2.21-2.10 (m,2H), 1.36 (s, 3H), 1.27 (s, 3H), 1.20 (s, 3H). LC/MS m/z 648.3 (M+H)⁺,2.23 min (method B). ¹H NMR (400 MHz, CHLOROFORM-d) Symbol 8.31 (dd,J=1.9, 1.1 Hz, 1H), 8.08 (d, J=8.3 Hz, 2H), 7.99 (d, J=1.3 Hz, 1H), 7.80(t, J=2.1 Hz, 1H), 7.33 (d, J=8.5 Hz, 2H), 5.79 (t, J=3.3 Hz, 1H), 5.66(dd, J=6.1, 2.9 Hz, 1H), 4.86 (t, J=6.1 Hz, 2H), 4.19 (dd, J=16.7, 3.9Hz, 1H), 3.85 (dd, J=16.7, 2.6 Hz, 1H), 3.75 (d, J=12.3 Hz, 1H), 3.31(t, J=6.3 Hz, 2H), 3.21-3.14 (m, 4H), 3.09-3.03 (m, 4H), 3.00 (d, J=12.3Hz, 1H), 2.24-2.11 (m, 2H), 1.40 (s, 3H), 1.31 (s, 3H), 1.21 (s, 3H)

Example B3 Preparation of(S)-4-(2-(3-amino-5-(2-(2-(1,1-dioxidothiomorpholino)ethyl)-2H-tetrazol-5-yl)phenyl)-5,5,8a-trimethyl-1,2,3,5,8,8a-hexahydroisoquinolin-6-yl)benzoicacid

To a medium yellow solution of(S)-4-(2-(3-(2-(2-(1,1-dioxidothiomorpholino)ethyl)-2H-tetrazol-5-yl)-5-nitrophenyl)-5,5,8a-trimethyl-1,2,3,5,8,8a-hexahydroisoquinolin-6-yl)benzoicacid (20 mg, 0.031 mmol) in absolute ethanol (900 μL) at RT was addedtin(II) chloride dihydrate (34.8 mg, 0.154 mmol) in a single portion.The mixture was warmed to 70-72° C. in an oil bath for an hour. Rapiddiscoloration was observed and the mixture turned into pale lemon yellowcolor. The resulted mixture was diluted with ethyl acetate, washed witha saturated aqueous solution of sodium bicarbonate. The aqueous phasewas then extracted three times with CH₂Cl₂. The organic layers werecombined and dried over sodium sulfate. The solvent was removed and theresidue was purified by prepHPLC. The fractions containing desiredproduct were collected and dried under reduced pressure to give thetitle compound (1 mg, 4.98%) as a solid. LC/MS m/z 618.41 (M+H)⁺, 2.01min (method B). ¹H NMR (400 MHz, METHANOL-d4) δ 8.00 (d, J=8.3 Hz, 2H),7.72 (s, 1H), 7.43 (s, 1H), 7.33 (d, J=8.3 Hz, 2H), 6.97 (s, 1H), 5.89(t, J=3.3 Hz, 1H), 5.66 (dd, J=5.6, 3.4 Hz, 1H), 4.92 (m, 2H), 4.13 (dd,J=16.8, 4.0 Hz, 1H), 3.82-3.78 (m, 1H), 3.76 (s, 1H), 3.27 (t, J=6.0 Hz,2H), 3.13-3.09 (m, 4H), 3.05 (d, J=6.5 Hz, 4H), 2.94 (d, J=12.0 Hz, 1H),2.19 (d, J=6.0 Hz, 2H), 1.42 (s, 3H), 1.32 (s, 3H), 1.22 (s, 3H).

Example B4 Preparation of(S)-4-(2-(3-(2-(2-(1,1-dioxidothiomorpholino)ethyl)-2H-tetrazol-5-yl)-5-(3-(1,1-dioxidothiomorpholino)propanamido)phenyl)-5,5,8a-trimethyl-1,2,3,5,8,8a-hexahydroisoquinolin-6-yl)benzoicacid

To a medium yellow solution of(S)-4-(2-(3-amino-5-(2-(2-(1,1-dioxidothiomorpholino)ethyl)-2H-tetrazol-5-yl)phenyl)-5,5,8a-trimethyl-1,2,3,5,8,8a-hexahydroisoquinolin-6-yl)benzoicacid (20 mg, 0.032 mmol) in CH₂Cl₂ (1 ml) at RT was added3-(1,1-dioxidothiomorpholino)propanoic acid (6.71 mg, 0.032 mmol) andHATU (24.62 mg, 0.065 mmol) followed by DIEA (16.96 μl, 0.097 mmol) andthe mixture was stirred for 3 h. The mixture was diluted with ethylacetate, washed with a saturated aqueous solution of sodium bicarbonate.The aqueous phase was then extracted three times with CH₂Cl₂. Theorganic layers were combine and dried over sodium sulfate. The solventwas removed and the residue was purified by prepHPLC. The fractionscontaining desired product were collected and dried under reducedpressure to give the title compound (2 mg, 7.66%) as a solid. LC/MS m/z808.53 (M+H)⁺, 2.13 min (method B).

Likewise the examples in Table 14 were prepared by the analogousaromatic nucleophilic substitution route as illustrated above inpreparations of examples B1 and B2 using(S)-6-(4-(methoxycarbonyl)phenyl)-5,5,8a-trimethyl-1,2,3,5,8,8a-hexahydroisoquinolin-2-iumchloride as the common starting material, and commercially availableelectrophiles instead of 3-fluoro-5-nitrobenzonitrile as indicated inthe table, followed by subsequent steps, 2, 3, 4.

TABLE 14 Obs Ex Reagent MW (M + 1)⁺ RT Met B5 4-fluorobenzonitrile602.27 603.38 2.30 B B6 2-fluorobenzonitrile 602.27 603.35 2.20 B B73,5-difluorobenzonitrile 459.21 460.40 1.99 D B83,5-difluorobenzonitrile 620.26 621.33 2.27 D B93,5-difluorobenzonitrile 618.26 619.32 1.80 D Ex = Example; MW =Molecular weight; Obs = Observed; RT = Retention time; Met = LC/MSMethod.

Example B10 Preparation of(S)-4,4′-(5,5,8a-trimethyl-3,5,8,8a-tetrahydroisoquinoline-2,6(1H)-diyl)dibenzoicacid

Step 1: Preparation of methyl(S)-4-(2-(4-cyanophenyl)-5,5,8a-trimethyl-1,2,3,5,8,8a-hexahydroisoquinolin-6-yl)benzoate

To a mixture of(S)-6-(4-(methoxycarbonyl)phenyl)-5,5,8a-trimethyl-1,2,3,5,8,8a-hexahydroisoquinolin-2-iumchloride (119 mg, 0.342 mmol) and 4-fluorobenzonitrile (317 mg, 2.62mmol) in the presence of anhydrous potassium carbonate (320 mg, 2.3mmol) in a resealable pressure tube was added DMF (4 mL), followed byflushing with nitrogen. The tube was sealed, placed in an oil bath at125° C. overnight. The resulted mixture was diluted with 50 mL of ethylacetate and washed twice with water (2×20 mL). The organic layers werecollected and evaporated to yield a solid which was purified by flashchromatography. The fractions containing desired product were collectedand dried under reduced pressure to give 130 mg of the title compound(88%) as a solid. LC/MS m/z 413.35 (M+H)⁺, 4.485 min (method C). ¹H NMR(400 MHz, CHLOROFORM-d) δ 8.04-7.94 (m, 2H), 7.56-7.47 (m, 2H),7.31-7.20 (m, 2H), 6.85 (d, J=9.0 Hz, 2H), 5.73 (t, J=3.3 Hz, 1H), 5.61(dd, J=6.4, 2.6 Hz, 1H), 4.05 (dd, J=16.8, 3.5 Hz, 1H), 3.94 (s, 3H),3.75 (dd, J=16.9, 2.9 Hz, 1H), 3.66 (d, J=12.5 Hz, 1H), 2.91 (d, J=12.5Hz, 1H), 2.17-2.02 (m, 2H), 1.32 (s, 3H), 1.26 (s, 3H), 1.15 (s, 3H).

Step 2

To a suspension of (S)-methyl4-(2-(4-cyanophenyl)-5,5,8a-trimethyl-1,2,3,5,8,8a-hexahydroisoquinolin-6-yl)benzoate(15 mg, 0.036 mmol) in ethanol (1 mL) was added a 40% w/w solution ofKOH (2 mL). The mixture was warmed to 80° C. for 7 hours. The resultedsolution was purified by prep. HPLC. The fractions containing desiredproduct were collected and dried under reduced pressure to give(S)-4,4′-(5,5,8a-trimethyl-3,5,8,8a-tetrahydroisoquinoline-2,6(1H)-diyl)dibenzoicacid (7 mg, 44.7%). LC/MS m/z 418.27 (M+H)⁺, 2.53 min (Method B). ¹H NMR(400 MHz, METHANOL-d₄) δ7.93-7.83 (m, 4H), 7.26-7.15 (m, 2H), 6.89 (d,J=8.8 Hz, 2H), 5.83 (t, J=3.4 Hz, 1H), 5.59 (dd, J=6.1, 2.9 Hz, 1H),4.04 (dd, J=17.1, 4.0 Hz, 1H), 3.79-3.56 (m, 2H), 2.78 (d, J=12.3 Hz,1H), 2.25-1.97 (m, 2H), 1.38 (s, 3H), 1.28 (s, 3H), 1.17 (s, 3H).

Likewise the examples in Table 15 were prepared by the analogousaromatic nucleophilic substitution route as illustrated above using(S)-6-(4-(methoxycarbonyl)phenyl)-5,5,8a-trimethyl-1,2,3,5,8,8a-hexahydroisoquinolin-2-iumchloride as the common starting material, and commercially availableelectrophiles instead of 4-fluorobenzonitrile indicated in the table.

TABLE 15 Obs Ex Reagent MW (M + 1)⁺ RT Met B11 2-chloropyrimidine 375.20376.23 2.21 B B12 ethyl 2-bromothiazole-5- 424.15 425.14 2.19 Bcarboxylate B13 2-chloro-4-methoxypyrimidine 405.21 406.20 1.94 B B14ethyl 2-bromothiazole-5- 452.18 453.11 2.39 B carboxylate* B153-fluoro-5-nitrobenzonitrile 462.18 463.21 2.43 B B16 ethyl2-bromothiazole-4- 424.15 425.14 2.18 D carboxylate B174-fluorobenzonitrile 416.21 417.25 2.21 B Ex = Example; MW = Molecularweight; Obs = Observed; RT = Retention time; Met = LC/MS Method. *sameas B12 except that a selective hydrolysis step to hydrolyze the methylester in the presence of an ethyl ester as described in Helv. Chim.Acta. 1974, 57, 987 was used.Section 4Method EStart % B=0, Final % B=100 over 2 minute gradient, hold at 100% BFlow Rate=0.8 mL/minWavelength=220 nmSolvent A=95% water, 5% methanol, 10 mM ammonium acetateSolvent B=5% water, 95% methanol, 10 mM ammonium acetateColumn=Xbridge C18, 3.5 μm, 2.1×50 mmMethod FStart % B=0, Final % B=100 over 2 minute gradient, hold at 100% BFlow Rate=1 mL/minWavelength=220 nmSolvent A=90% water, methanol, 0.1% TFASolvent B=10% water, 90% methanol, 0.1% TFAColumn=Phenomenex Luna C18, 3 μm, 2.0×30 mm

Example C1 Preparation of4-((4aS,8aS)-2-(2-((S)-2-((2-(1,1-dioxidothiomorpholino)ethyl)carbamoyl)pyrrolidin-1-yl)-2-oxoacetyl)-5,5,8a-trimethyl-1,2,3,4,4a,5,8,8a-octahydroisoquinolin-6-yl)benzoicacid

Step 1: Preparation of (4aR,6S,8aS)-ethyl6-hydroxy-5,5,8a-trimethyloctahydroisoquinoline-2(1H)-carboxylate and(4aS,6S,8aS)-ethyl6-hydroxy-5,5,8a-trimethyloctahydroisoquinoline-2(1H)-carboxylate

To a solution of (6S,8aS)-ethyl6-hydroxy-5,5,8a-trimethyl-3,5,6,7,8,8a-hexahydroisoquinoline-2(1H)-carboxylate(5.2 g, 19.45 mmol) in ethanol (100 mL) was added acetic acid (1.1 mL,19.5 mmol) and Pd/C (2.07 g, 1.95 mmol). The mixture was attached to aPARR shaker and was pressurized to 50 psi with hydrogen. After 24 h themixture was removed from the PARR shaker. TLC indicated some startingmaterial still remained so the mixture was degassed, the sides of theflask were washed with 10 mL of MeOH and an additional 2.0 g of Pd/Cwere added. The mixture was again put on the PARR shaker under 60 psi ofhydrogen. The mixture was filtered through a pad of celite to remove thesolids and the filtrate was concentrated under reduced pressure. Theresidue was purified by flash chromatography using a 300 g silica gelcolumn and a 0-30% EtOAc in toluene gradient. The fractions containingthe expected product were combined and concentrated under reducedpressure to give 2.55 g of the major product as a clear, colorless oil(Rf=0.23, 2:8 EtOAc/toluene, stained with Hanessian's stain) and 0.69 gof the minor product as a clear, colorless oil, which upon standingpartially crystallized. The fractions containing a mixture ofdiastereomers were combined and were concentrated under reduced pressurethen were repurified by flash chromatography using a 0-30% EtOAc intoluene gradient and a 240 g silica gel column. The fractions containingeach diastereomer were combined and concentrated under reduced pressure.To give an additional 0.59 g of the major product, (4aR,6S,8aS)-ethyl6-hydroxy-5,5,8a-trimethyloctahydroisoquinoline-2(1H)-carboxylate (3.14g total, 60% yield), and 0.51 g of the minor product, (4aS,6S,8aS)-ethyl6-hydroxy-5,5,8a-trimethyloctahydroisoquinoline-2(1H)-carboxylate (1.2 gtotal, 23% yield). Major product: ¹H NMR (500 MHz, chloroform-d) δ4.42-4.21 (m, 1H), 4.19-4.06 (m, 2H), 3.86-3.61 (m, 1H), 3.30-3.23 (m,1H), 2.76-2.57 (m, 1H), 2.36-2.21 (m, 1H), 1.76-1.60 (m, 2H), 1.58-1.49(m, 2H), 1.49-1.35 (m, 2H), 1.32-1.12 (m, 4H), 0.99 (s, 3H), 0.98-0.92(m, 4H), 0.79 (s, 3H). Minor product: ¹H NMR (500 MHz, chloroform-d) δ4.20-3.96 (m, 3H), 3.63-3.44 (m, 2H), 2.75-2.53 (m, 2H), 1.77-1.62 (m,4H), 1.51 (qd, J=12.6, 4.7 Hz, 1H), 1.33-1.15 (m, 6H), 1.12 (s, 3H),1.08 (s, 3H), 1.02 (s, 3H).

Step 2: Preparation of(4aR,6S,8aS)-5,5,8a-trimethyldecahydroisoquinolin-6-ol

A solution of (4aR,6S,8aS)-ethyl6-hydroxy-5,5,8a-trimethyloctahydroisoquinoline-2(1H)-carboxylate (0.585g, 2.17 mmol) in THF (15 mL) was cooled to 0° C. To the solution wasadded methyllithium (1.6M in ether, 6.79 mL, 10.86 mmol). The mixturewas stirred at 0° C. for 3 h then was carefully quenched with water (15mL) and extracted with dichloromethane (3×25 mL). The combined organiclayers were dried over sodium sulfate, filtered and concentrated underreduced pressure to give the crude product as an orange solid. The crudeproduct was used in the next step with no additional purification.

Step 3: Preparation of (4aR,6S,8aS)-tert-butyl6-hydroxy-5,5,8a-trimethyloctahydroisoquinoline-2(1H)-carboxylate

To a solution of the crude(4aR,6S,8aS)-5,5,8a-trimethyldecahydroisoquinolin-6-ol in 1,4-dioxane (7mL) was added 1 M NaOH (7.30 mL, 7.30 mmol) followed by Boc₂O (1.24 mL,5.35 mmol). The mixture was stirred at rt for 16.5 h then was dilutedwith 20 mL of water and extracted with dichloromethane (3×40 mL). Thecombined organic layers were dried over sodium sulfate, filtered andconcentrated under reduced pressure to give the title product. The crudeproduct was used in the next step with no additional purification. LCMS:m/e 298.06 (M+H)⁺, 1.70 min (Method E).

Step 4: Preparation of (4aR,8aS)-tert-butyl5,5,8a-trimethyl-6-oxooctahydroisoquinoline-2(1H)-carboxylate

To a solution of the crude (4aR,6S,8aS)-tert-butyl6-hydroxy-5,5,8a-trimethyloctahydroisoquinoline-2(1H)-carboxylate (0.66g, 2.219 mmol) from the previous step in dichloromethane (15 mL) wasadded pyridinium chlorochromate (0.717 g, 3.33 mmol). The mixture wasstirred at rt for 3 h, then was filtered through a pad of silica gel andcelite (washed with 1:1 ethyl acetate:hexanes). The filtrate wasconcentrated under reduced pressure to give the title product (0.47 g,1.59 mmol, 73% over 3 steps). ¹H NMR (400 MHz, chloroform-d) δ 4.51-4.17(m, 1H), 4.01-3.66 (m, 1H), 2.80-2.53 (m, 2H), 2.46-2.22 (m, 2H), 1.47(s, 9H), 1.75-1.23 (m, 5H), 1.13 (s, 3H), 1.09 (s, 3H), 1.04 (s, 3H).¹³C NMR (101 MHz, chloroform-d) δ 215.5, 154.9, 79.5, 59.3, 52.5, 47.4,36.3, 34.9, 34.4, 28.5, 27.4, 25.2, 22.2, 21.4, 17.2.

Step 5: Preparation of (4aR,8aS)-tert-butyl5,5,8a-trimethyl-6-(trifluoromethylsulfonyloxy)-3,4,4a,5,8,8a-hexahydroisoquinoline-2(1H)-carboxylate

A solution of (4aR,8aS)-tert-butyl5,5,8a-trimethyl-6-oxooctahydroisoquinoline-2(1H)-carboxylate (0.464 g,1.571 mmol) in THF (10 mL) was cooled to −78° C. To the solution wasadded KHMDS (0.5 M in toluene, 6.28 mL, 3.14 mmol). The mixture wasstirred for 15 minutes at −78° C. and a solution ofN-phenylbis(trifluoromethanesulphonimide) (0.617 g, 1.728 mmol) in THF(5 mL) and toluene (5 mL) was added. The mixture was stirred at −78° C.for 3 h then an additional 0.1 g ofN-Phenylbis(trifluoromethanesulphonimide) was added. After 1 h ofadditional stirring, the reaction was quenched with water (30 mL) andextracted with ethyl acetate (3×50 mL). The combined organic layers weredried over sodium sulfate, filtered and concentrated under reducedpressure. The residue was adsorbed to silica gel and was purified byflash chromatography using a 0-20% ethyl acetate in hexanes gradient anda 40 g silca gel colmn. The fractions containing the expected productwere combined and concentrated under reduced pressure. The title productwas isolated as a clear, colorless oil (0.468 g, 1.095 mmol, 69.7%yield). NMR (500 MHz, chloroform-d) δ 5.68 (dd, J=6.0, 2.9 Hz, 1H),4.46-4.16 (m, 1H), 4.02-3.74 (m, 1H), 2.77-2.25 (m, 2H), 2.01-1.89 (m,2H), 1.47 (s, 9H), 1.68-1.41 (m, 3H), 1.14 (s, 3H), 1.02 (s, 3H), 1.01(s, 3H).

Step 6: Preparation of (4aS,8aS)-tert-butyl6-(4-(tert-butoxycarbonyl)phenyl)-5,5,8a-trimethyl-3,4,4a,5,8,8a-hexahydroisoquinoline-2(1H)-carboxylate

To a solution of (4aR,8aS)-tert-butyl5,5,8a-trimethyl-6-(trifluoromethylsulfonyloxy)-3,4,4a,5,8,8a-hexahydroisoquinoline-2(1H)-carboxylate(0.46 g, 1.08 mmol) in 1,4-dioxane (8.0 mL) was added sodium carbonatemonohydrate (0.40 g, 3.23 mmol), 4-tert-butoxycarbonylphenylboronic acid(0.30 g, 1.35 mmol), and palladium tetrakis (0.037 g, 0.032 mmol). Themixture was diluted with water (2.0 mL), flushed with nitrogen andheated to 85° C. After 3 h of heating, the mixture was cooled to rt,diluted with 25 mL of water and was extracted with dichloromethane (3×30mL). The combined organic layers were dried over sodium sulfate,filtered and concentrated under reduced pressure. The residue wasadsorbed to silica gel and was purified by flash chromatography using a0-25% ethyl acetate in hexanes gradient and a 25 g silica gel column.The fractions containing the expected product were combined andconcentrated under reduced pressure to give the title product as aclear, colorless film. LCMS: m/e 456.2 (M+H)⁺, 2.76 min (Method E). ¹HNMR (400 MHz, chloroform-d) δ 7.90 (d, J=8.3 Hz, 2H), 7.21-7.16 (m, 2H),5.38 (dd, J=5.3, 3.0 Hz, 1H), 4.49-4.16 (m, 1H), 4.02-3.72 (m, 1H),2.85-2.30 (m, 2H), 1.96-1.81 (m, 2H), 1.60 (s, 9H), 1.49 (s, 9H),1.71-1.42 (m, 3H), 1.09 (s, 3H), 0.96 (s, 3H), 0.90 (s, 3H).

Step 7: Preparation of tert-butyl4-((4aS,8aS)-5,5,8a-trimethyl-1,2,3,4,4a,5,8,8a-octahydroisoquinolin-6-yl)benzoate

To a solution of (4aS,8aS)-tert-butyl6-(4-(tert-butoxycarbonyl)phenyl)-5,5,8a-trimethyl-3,4,4a,5,8,8a-hexahydroisoquinoline-2(1H)-carboxylate(0.32 g, 0.702 mmol) in ethyl acetate (3 mL) was added HCl (4M indioxane, 1 mL, 4.00 mmol). The mixture was stirred at rt in a sealedvessel for 5 h, then the vessel was uncapped and was stirred overnightat rt. LC/MS indicated the reaction was not yet complete so anadditional 5 mL of EtOAc and HCl (4M in dioxane) (1 mL, 4.00 mmol) wasadded and the mixture was stirred for a second night. After stirringovernight, LC/MS was inconclusive, so TFA was added (0.271 mL, 3.51mmol) and the mixture was stirred at rt for three days. The mixture wasconcentrated under reduced pressure then was used in the next step withno additional purification. LCMS: m/e 356.23 (M+H)⁺, 2.16 min (MethodE).

Step 8: Preparation of tert-butyl4-((4aS,8aS)-2-(2-methoxy-2-oxoacetyl)-5,5,8a-trimethyl-1,2,3,4,4a,5,8,8a-octahydroisoquinolin-6-yl)benzoate

To a suspension of tert-butyl4-((4aS,8aS)-5,5,8a-trimethyl-1,2,3,4,4a,5,8,8a-octahydroisoquinolin-6-yl)benzoate,HCl (0.27 g, 0.689 mmol) in DCE (5 mL) was added DIEA (0.602 mL, 3.44mmol) and methyl oxalyl chloride (127 mL, 1.378 mmol). Upon addition ofthe methyl oxalyl chloride, the solids dissolved. The sides of the flaskwere rinsed with an additional 3 mL of DCE and the clear, yellowsolution was stirred at 11 for 30 minutes. HPLC showed completeconsumption of the starting material so the mixture was diluted withwater (20 mL) and was extracted with dichloromethane (3×20 mL). Thecombined organic layers were dried over sodium sulfate, filtered andconcentrated under reduced pressure. The mixture was filtered through apad of celite and silica gel (washed with 1:1 ethyl acetate:hexanes) andthe filtrate was concentrated under reduced pressure to give the titleproduct as a colorless foam (0.29 g, 0.657 mmol, 94% yield over twosteps). LCMS: m/e 442.26 (M+H)⁺, 2.48 min (Method E).

Step 9: Preparation of2-((4aS,8aS)-6-(4-(tert-butoxycarbonyl)phenyl)-5,5,8a-trimethyl-3,4,4a,5,8,8a-hexahydroisoquinolin-2(1H)-yl)-2-oxoaceticacid

To a solution of tert-butyl4-((4aS,8aS)-2-(2-methoxy-2-oxoacetyl)-5,5,8a-trimethyl-1,2,3,4,4a,5,8,8a-octahydroisoquinolin-6-yl)benzoate(0.283 g, 0.641 mmol) in THF (5 mL) was added NaOH (1N, 3.2 mL, 3.2mmol). The mixture was stirred at rt for 3.5 h then was neutralized with10 mL 1N HCl and extracted with dichloromethane (3×15 mL). The combinedorganic layers were dried over sodium sulfate, filtered and concentratedunder reduced pressure. The title product was isolated as a colorlessfoam (0.275 g, 0.643 mmol, 100% yield). LCMS: m/e 428.22 (M+H)⁺, 2.24min (Method E).

Step 10: Preparation of (S)-methyl1-(2-((4aS,8aS)-6-(4-(tert-butoxycarbonyl)phenyl)-5,5,8a-trimethyl-3,4,4a,5,8,8a-hexahydroisoquinolin-2(1H)-yl)-2-oxoacetyl)pyrrolidine-2-carboxylate

To a solution of2-((4a5,8aS)-6-(4-(tert-butoxycarbonyl)phenyl)-5,5,8a-trimethyl-3,4,4a,5,8,8a-hexahydroisoquinolin-2(1H)-yl)-2-oxoaceticacid (0.27 g, 0.632 mmol) in dichloromethane (6 mL) was added DIEA(0.551 mL, 3.16 mmol), L-proline methyl ester hydrochloride (0.126 g,0.758 mmol), and o-Benzotriazol-1-yl-N,N,N′,N′-tetramethyluroniumtetrafluoroborate (0.304 g, 0.947 mmol). The mixture was stirred at for15.5 h, then was diluted with 15 mL of water and extracted withdichloromethane (3×15 mL). The combined organic layers were dried oversodium sulfate, filtered and concentrated under reduced pressure. Theresidue was adsorbed to silica gel and was purified by flashchromatography using a 0-65% ethyl acetate in hexanes gradient and a 25g silica gel column. The fractions containing the expected product werecombined and concentrated under reduced pressure to give the titleproduct product as a white foam (0.212 g, 0.394 mmol, 62.3% yield).LCMS: m/e 538.98 (M+H)⁺, 2.48 min (Method E).

Step 11: Preparation of(S)-1-(2-((4aS,8aS)-6-(4-(tert-butoxycarbonyl)phenyl)-5,5,8a-trimethyl-3,4,4a,5,8,8a-hexahydroisoquinolin-2(1H)-yl)-2-oxoacetyl)pyrrolidine-2-carboxylicacid

To a solution of (S)-methyl1-(2-((4aS,8aS)-6-(4-(tert-butoxycarbonyl)phenyl)-5,5,8a-trimethyl-3,4,4a,5,8,8a-hexahydroisoquinolin-2(1H)-yl)-2-oxoacetyl)pyrrolidine-2-carboxylate(0.212 g, 0.394 mmol) in THF (5 mL) was added NaOH (1N, 2 ml, 2.000mmol). The mixture was stirred at rt for 16 h then was diluted with 10mL of 1N HCl and extracted with dichloromethane (3×15 mL). The combinedorganic layers were dried over sodium sulfate, filtered and concentratedunder reduced pressure. The drying agent was removed by filtration, andthe filtrate was concentrated under reduced pressure to give the titlecompound as a white solid (0.188 g, 0.358 mmol, 91% yield). LCMS: m/e525.30 (M+H)⁺, 2.27 min (Method E).

Step 12: Preparation of tert-butyl4-((4aS,8aS)-2-(2-((S)-2-((2-(1,1-dioxidothiomorpholino)ethyl)carbamoyl)pyrrolidin-1-yl)-2-oxoacetyl)-5,5,8a-trimethyl-1,2,3,4,4a,5,8,8a-octahydroisoquinolin-6-yl)benzoate

To a solution of(S)-1-(2-((4aS,8aS)-6-(4-(tert-butoxycarbonyl)phenyl)-5,5,8a-trimethyl-3,4,4a,5,8,8a-hexahydroisoquinolin-2(1H)-yl)-2-oxoacetyl)pyrrolidine-2-carboxylicacid (0.02 g, 0.038 mmol) in DCE (1 mL) was added DIEA (0.033 mL, 0.191mmol) followed by N-(2-aminoethyl) thiomorpholine 1,1-dioxide (10.19 mg,0.057 mmol) and o-Benzotriazol-1-yl-N,N,N′,N′-tetramethyluroniumtetrafluoroborate (0.018 g, 0.057 mmol). The mixture was stirred at rtover the weekend for 64 h then was diluted with 5 mL of water andextracted with dichloromethane (3×5 mL). The combined organic layerswere dried over sodium sulfate, filtered and concentrated under reducedpressure. The residue was purified by prep HPLC. The fractionscontaining the expected product were combined and concentrated underreduced pressure to give the title product as an off-white solid (16.5mg, 0.024 mmol, 63% yield). LCMS: m/e 685.38 (M+H)⁺, 2.36 min (MethodE).

Step 13

To a solution of tert-butyl4-((4aS,8aS)-2-(2-((S)-2-(2-(1,1-dioxidothiomorpholino)ethyl)carbamoyl)pyrrolidin-1-yl)-2-oxoacetyl)-5,5,8a-trimethyl-1,2,3,4,4a,5,8,8a-octahydroisoquinolin-6-yl)benzoate(16.5 mg, 0.024 mmol) in DCM (1 mL) was added TFA (9.28 μl, 0.120 mmol)and triethylsilane (3.85 μl, 0.024 mmol). The mixture was stirred at rt.After 1 h an additional 0.1 mL of TFA was added. After 3 h of stirringthe mixture was concentrated under a stream of nitrogen. The residue waspurified by prep HPLC. The fractions containing the expected productwere combined and concentrated under reduced pressure to give4-((4aS,8aS)-2-(2-((S)-2-((2-(1,1-dioxidothiomorpholino)ethyl)carbamoyl)pyrrolidin-1-yl)-2-oxoacetyl)-5,5,8a-trimethyl-1,2,3,4,4a,5,8,8a-octahydroisoquinolin-6-yl)benzoicacid as a clear, colorless foam (13.1 mg, 0.021 mmol, 88% yield). LCMS:m/e 629.24 (M+H)⁺, 1.56 min (Method E).

Example C2 Preparation of4-((4aS,8aS)-2-(2-((S)-2-((3-(1,1-dioxidothiomorpholino)propyl)carbamoyl)pyrrolidin-1-yl)-2-oxoacetyl)-5,5,8a-trimethyl-1,2,3,4,4a,5,8,8a-octahydroisoquinolin-6-yl)benzoicacid

Step 1: Preparation of tert-butyl4-((4aS,8aS)-2-(2-((S)-2-((3-(1,1-dioxidothiomorpholino)propyl)carbamoyl)pyrrolidin-1-yl)-2-oxoacetyl)-5,5,8a-trimethyl-1,2,3,4,4a,5,8,8a-octahydroisoquinolin-6-yl)benzoate

To a solution of(S)-1-(2-((4aS,8aS)-6-(4-(tert-butoxycarbonyl)phenyl)-5,5,8a-trimethyl-3,4,4a,5,8,8a-hexahydroisoquinolin-2(1H)-yl)-2-oxoacetyl)pyrrolidine-2-carboxylicacid (0.02 g, 0.038 mmol) in DCE (1 mL) was added DIEA (0.033 mL, 0.191mmol) followed by thiomorpholine, 4-(3-aminoropyl)-1,1-dioxide (10.99mg, 0.057 mmol) and o-benzotriazol-1-yl-N,N,N′,N′-tetramethyluroniumtetrafluoroborate (0.018 g, 0.057 mmol). The mixture was stirred at rtfor 64 h, then was diluted with 5 mL of water and extracted withdichloromethane (3×5 mL). The combined organic layers were dried oversodium sulfate, filtered and concentrated under reduced pressure. Theresidue was purified by prep HPLC. The fractions containing the expectedproduct were combined and concentrated under reduced pressure to givethe title product (18.5 mg, 0.026 mmol, 69% yield). LCMS: m/e 699.46(M+H)⁺, 2.37 min (Method E).

Step 2

To a solution of tert-butyl4-((4aS,8aS)-2-(2-((S)-2-((3-(1,1-dioxidothiomorpholino)propyl)carbamoyl)pyrrolidin-1-yl)-2-oxoacetyl)-5,5,8a-trimethyl-1,2,3,4,4a,5,8,8a-octahydroisoquinolin-6-yl)benzoate(18.5 mg, 0.026 mmol) in DCM (1 mL) was added triethylsilane (4.23 μl,0.026 mmol) and TFA (10.20 μl, 0.132 mmol). The mixture was stirred atrt. After 1 h of stirring an additional 0.1 mL of TFA was added. After 3h of stirring, the mixture was concentrated under a stream of nitrogen.The residue was purified by prep HPLC. The fractions containing theexpected product were combined and concentrated under reduced pressureto give the title product as a clear, colorless foam. (10.8 mg, 0.017mmol, 65% yield). LCMS: m/e 643.23 (M+H)⁺, 1.59 min (Method E).

Example C3 Preparation of(S)-4-(2-(4-(aminomethyl)-4-phenylcyclohexyl)-5,5,8a-trimethyl-1,2,3,5,8,8a-hexahydroisoquinolin-6-yl)benzoicacid

Step 1: Preparation of (S)-tert-butyl5,5,8a-trimethyl-6-(((trifluoromethyl)sulfonyl)oxy)-3,5,8,8a-tetrahydroisoquinoline-2(1H)-carboxylate

To a solution of (S)-tert-butyl5,5,8a-trimethyl-6-oxo-1,5,6,7,8,8a-hexahydroisoquinoline-2(3H)-carboxylate(5.4 g, 18.40 mmol) in THF (100 mL) at −78° C. was added KHMDS (0.91M inTHF, 30.3 mL, 27.6 mmol). The mixture was stirred for 1 hour, then1,1,1-trifluoro-N-phenyl-N-((trifluoromethyl)sulfonyl)methanesulfonamide(7.23 g, 20.25 mmol) in THF (20 ml) was added and the reaction stirredat −78° C. for 2 hour. TLC indicated sm was consumed so the reactionmixture was quenched with water and extracted with ethyl acetate. Thecombined organic layers were dried over sodium sulfate, filtered andconcentrated under reduced pressure. The residue was purified usingflash chromatography with a 20-50% ethyl acetate/hexanes mobile phase.The fractions containing the product were combine and concentrated underreduced pressure to give the title product as yellow oil (5.0 g, 11.75mmol, 64% yield). ¹H NMR (400 MHz, chloroform-d) δ 5.79 (dd, J=6.0, 3.3Hz, 1H), 5.69-5.55 (m, 1H), 4.45-4.15 (m, 1H), 4.00-3.58 (m, 2H),2.75-2.54 (m, 1H), 2.05 (br. s., 2H), 1.49 (s, 9H), 1.30 (s, 3H), 1.27(br. s., 3H), 1.19 (s, 3H).

Step 2: Preparation of (S)-tert-butyl6-(4-(methoxycarbonyl)phenyl)-5,5,8a-trimethyl-3,5,8,8a-tetrahydroisoquinoline-2(1H)-carboxylate

A mixture of (S)-tert-butyl5,5,8a-trimethyl-6-(((trifluoromethyl)sulfonyl)oxy)-3,5,8,8a-tetrahydroisoquinoline-2(1H)-carboxylate(2.0 g, 4.70 mmol), (4-(methoxycarbonyl)phenyl)boronic acid (1.27 g,7.05 mmol), Pd(PPh₃)₄ (0.163 g, 0.141 mmol) and sodium carbonate (4.98g, 47.0 mmol) in 1,4-dioxane (20 mL) and water (20.00 mL) was stirred at90° C. for 1 hour. The reaction mixture was worked up and the residuewas purified by flash chromatography to provide the title product aswhite solid (1.3 g, 3.16 mmol, 67% yield). LCMS: m/e 412.19 (M+H)⁺, 2.49min (Method F).

Step 3: Preparation of (S)-methyl4-(5,5,8a-trimethyl-1,2,3,5,8,8a-hexahydroisoquinolin-6-yl)benzoate

A mixture of (S)-tert-butyl6-(4-(methoxycarbonyl)phenyl)-5,5,8a-trimethyl-3,5,8,8a-tetrahydroisoquinoline-2(1H)-carboxylate(1.3 g, 3.16 mmol) and HCl (4M, 7.90 mL, 31.6 mmol) in THF (20 mL) wasstirred at 20° C. for 40 hour. LCMS indicated the formation of desiredproduct so the reaction mixture was concentrated under reduced pressureto provide the desired product as white solid (0.9 g, 2.89 mmol, 91%yield). LCMS: m/e 312.23 (M+H)⁺, 1.79 min (Method F).

Step 4: Preparation of (S)-methyl4-(2-(4-(((tert-butoxycarbonyl)amino)methyl)-4-phenylcyclohexyl)-5,5,8a-trimethyl-1,2,3,5,8,8a-hexahydroisoquinolin-6-yl)benzoate

A mixture of (S)-methyl4-(5,5,8a-trimethyl-1,2,3,5,8,8a-hexahydroisoquinolin-6-yl)benzoate (360mg, 1.156 mmol), tert-butyl ((4-oxo-1-phenylcyclohexyl)methyl)carbamate(421 mg, 1.387 mmol) and titanium(IV) isopropoxide (0.339 mL, 1.156mmol) in dichloromethane (100 mL) was stirred at 20° C. for 1 h, thensodium triacetoxyhydroborate (490 mg, 2.312 mmol) was added. Thereaction mixture was stirred for 20 hours at room temperature, then wasworked up. The residue was purified by flash chromatography using a0-30% ethyl acetate/hexanes gradient to provide the title product aswhite solid (0.120 g, 0.200 mmol, 17% yield). LCMS: m/e 599.4 (M+H)⁺,2.16 min (Method F).

Step 5: Preparation of (S)-methyl4-(2-(4-(aminomethyl)-4-phenylcyclohexyl)-5,5,8a-trimethyl-1,2,3,5,8,8a-hexahydroisoquinolin-6-yl)benzoate

A mixture of (S)-methyl4-(2-(4-(((tert-butoxycarbonyl)amino)methyl)-4-phenylcyclohexyl)-5,5,8a-trimethyl-1,2,3,5,8,8a-hexahydroisoquinolin-6-yl)benzoate(120 mg, 0.200 mmol) and HCl (4M, 0.501 mL, 2.004 mmol) in THF (2 mL)was stirred at 20° C. for 35 h. The reaction mixture was concentratedunder reduced pressure to provide the title product as white solid(0.060 g, 0.120 mmol, 60%). LCMS: m/e 499.3 (M+H)⁺, 1.85 min (Method F).

Step 6

A mixture of (S)-methyl4-(2-(4-(aminomethyl)-4-phenylcyclohexyl)-5,5,8a-trimethyl-1,2,3,5,8,8a-hexahydroisoquinolin-6-yl)benzoate(6 mg, 0.012 mmol) and NaOH (1M, 0.120 mL, 0.120 mmol) in 1,4-dioxane(1.0 mL) was stirred at 80° C. for 3 h. The reaction mixture wasfiltered and purified by preparative HPLC to provide(S)-4-(2-(4-(aminomethyl)-4-phenylcyclohexyl)-5,5,8a-trimethyl-1,2,3,5,8,8a-hexahydroisoquinolin-6-yl)benzoicacid as white solid (2.0 mg, 0.004 mmol, 33% yield). LCMS: m/e 485.27(M+H)⁺, 1.74 min (method F).

Example C4 Preparation of(S)-4-(2-(4-((bis(2-(1,1-dioxidothiomorpholino)ethyl)amino)methyl)-4-phenylcyclohexyl)-5,5,8a-trimethyl-1,2,3,5,8,8a-hexahydroisoquinolin-6-yl)benzoicacid

Step 1: Preparation of (S)-methyl4-(2-(4-((bis(2-(1,1-dioxidothiomorpholino)ethyl)amino)methyl)-4-phenylcyclohexyl)-5,5,8a-trimethyl-1,2,3,5,8,8a-hexahydroisoquinolin-6-yl)benzoate

A mixture of (S)-methyl4-(2-(4-(aminomethyl)-4-phenylcyclohexyl)-5,5,8a-trimethyl-1,2,3,5,8,8a-hexahydroisoquinolin-6-yl)benzoate(92526-066) (10 mg, 0.020 mmol), 4-(2-chloroethyl)thiomorpholine1,1-dioxide (7.93 mg, 0.040 mmol), potassium phosphate (17.03 mg, 0.080mmol) and potassium iodide (6.66 mg, 0.040 mmol) in acetonitrile (1 mL)was heated to 120° C. in a sealed pressure vessel for 4 hour. Thereaction mixture was worked up. The title product was isolated as ayellow oil (10 mg, 0.012 mmol, 60% yield). LCMS: m/e 821.39 (M+H)⁺, 1.86min (Method F).

Step 2

A mixture of (S)-methyl4-(2-(4-((bis(2-(1,1-dioxidothiomorpholino)ethyl)amino)methyl)-4-phenylcyclohexyl)-5,5,8a-trimethyl-1,2,3,5,8,8a-hexahydroisoquinolin-6-yl)benzoate(10 mg, 0.012 mmol) and NaOH (1M, 0.122 mL, 0.122 mmol) in 1,4-dioxane(1.0 mL) was stirred at 80° C. for 3 h. The mixture was cooled to rt,filtered and purified by preparative HPLC to provide(S)-4-(2-(4-((bis(2-(1,1-dioxidothiomorpholino)ethyl)amino)methyl)-4-phenylcyclohexyl)-5,5,8a-trimethyl-1,2,3,5,8,8a-hexahydroisoquinolin-6-yl)benzoicacid as a white solid (3.6 mg, 0.0044 mmol, 37% yield). LCMS: m/e 807.39(M+H)⁺, 1.68 min (Method F).

Example C5 Preparation of(S)-4-(2-(4-(((tert-butoxycarbonyl)amino)methyl)-4-phenylcyclohexyl)-5,5,8a-trimethyl-1,2,3,5,8,8a-hexahydroisoquinolin-6-yl)benzoicacid

A mixture of (S)-methyl4-(2-(4-(((tert-butoxycarbonyl)amino)methyl)-4-phenylcyclohexyl)-5,5,8a-trimethyl-1,2,3,5,8,8a-hexahydroisoquinolin-6-yl)benzoate(32 mg, 0.027 mmol) and NaOH (1M, 0.267 ml, 0.267 mmol) in 1,4-dioxane(1.0 ml) was stirred heated to 80° C. for 3 h. The reaction mixture wasfiltered and purified by preparative HPLC to provide the desired productas white solid (3.5 mg, 0.0059 mmol, 22% yield). LCMS: m/e 585.45(M+H)⁺, 2.09 min (Method F).

Results

Biology Data for the Examples

-   -   “μM” means micromolar;    -   “mL” means milliliter;    -   “μl” means microliter;    -   “mg” means milligram;    -   “μg” means microgram;

The materials and experimental procedures used to obtain the resultsreported in Tables 16 and 17 are described below.

HIV Cell Culture Assay—

MT-2 cells and 293T cells were obtained from the NIH AIDS Research andReference Reagent Program. MT-2 cells were propagated in RPMI 1640 mediasupplemented with 10% heat inactivated fetal bovine serum, 100 μg/mlpenicillin G and up to 100 units/ml streptomycin. The 293T cells werepropagated in DMEM media supplemented with 10% heat inactivated fetalbovine serum (FBS), 100 units/ml penicillin G and 100 μg/mlstreptomycin. The proviral DNA clone of NL₄₋₃ was obtained from the NIHAIDS Research and Reference Reagent Program. A recombinant NL₄₋₃ virus,in which a section of the nef gene from NL₄₋₃ was replaced with theRenilla luciferase gene, was used as a reference virus. In addition,residue Gag P373 was converted to P373S. Briefly, the recombinant viruswas prepared by transfection of the altered proviral clone of NL₄₋₃.Transfections were performed in 293T cells using LipofectAMINE PLUS fromInvitrogen (Carlsbad, Calif.), according to manufacturer's instruction.The virus was titered in MT-2 cells using luciferase enzyme activity asa marker. Luciferase was quantitated using the Dual Luciferase kit fromPromega (Madison, Wis.), with modifications to the manufacturer'sprotocol. The diluted Passive Lysis solution was pre-mixed with there-suspended Luciferase Assay Reagent and the re-suspended Stop & GloSubstrate (2:1:1 ratio). Fifty (50) μL of the mixture was added to eachaspirated well on assay plates and luciferase activity was measuredimmediately on a Wallac TriLux (Perkin-Elmer). Antiviral activities ofinhibitors toward the recombinant virus were quantified by measuringluciferase activity in cells infected for 4-5 days with NLRlucrecombinants in the presence serial dilutions of the inhibitor. The EC₅₀data for the compounds is shown in Table 17. Table 16 is the key for thedata in Table 17.

Results:

TABLE 16 Biological Data Key for EC₅₀ Compounds with Compounds with EC50Compounds with EC50 EC50 <0.5 μM >0.5 μM and <3 μM >3 μM Group “A” Group“B” Group “C”

TABLE 17 Biological data 10% FBS EC₅₀ Ex Structure (uM)   1

C   2

C   3

C   4

C   5

C   6

C   7

C   8

C   9

C  10

C  11

0.46  12

C  13

C  14

C  15

C  16

C  17

1.69  18

C  19

C  20

C  21

C  22

C  23

C  24

C  25

C  26

0.63  27

C  28

C  29

C  30

2.27  31

C  32

0.66  33

C  34

C  35

C  36

C  37

C  38

C  39

1.49  40

C  41

C  42

C  43

C  44

0.52  45

C  46

0.25  47

1.07  48

0.27  49

1.18  50

0.29  51

0.87  52

3.62  53

C  54

 0.610  55

3.04  56

A  57

 0.148  58

A  59

 1.047  60

B  61

C  62

C  63

C  64

1.06  65

2.81  66

C  67

C  68

C  69

C  70

C  71

C  72

C  73

C  74

0.34  75

0.19  76

0.98  77

C  78

0.27  79

C  80

 0.179  81

B  82

A  83

A  84

 0.050  85

A  86

A  87

 0.101  88

A  89

 0.067  90

C  91

C  92

 0.008  93

A  94

1.37  95

2.70  96

1.35  97

 0.051  98

A  99

 0.016 100

2.81 101

2.98 A1

C A30

1.08  A36

0.38  A40

C  A46

1.32  A58

1.85  A66

C  A71

1.30  A79

0.87  A86

C  A91

 0.711 A111

C A112

 1.104 A114

 0.052 A168

A A185

 0.123 A195

A A197

 0.147 A204

 0.309 A219

 0.150 A254

A A260

 0.298 A265

A A266

A A267

B A268

 0.014 A270

 0.014 A271

A A272

A A273

 0.063 A274

C A275

1.70 A277

2.25 A278

4.96 A279

0.39 A280

0.55 A281

0.95 A283

1.37 A286

C A290

C A293

C A294

C A296

C A298

 0.060 A299

A A309

 0.171 A311

 0.218 A314

B A315

 0.127 A318

A A320

 0.183 A324

A A325

 0.235 A326

 0.257 A332

A A334

A A338

B  B1

 0.024  B2

 0.760  B3

C  B4

 1.702  B5

C  B6

 0.045  B7

C  B8

A  B9

1.17  B10

C  B11

C  B12

C  B13

2.7   B14

B  B15

C  B16

 1.478  B17

C  C1

C  C2

C  C3

 0.1504  C4

>3   

The disclosure is not limited to the foregoing illustrative examples andthe examples should be considered in all respects as illustrative andnot restrictive, reference being made to the appended claims, ratherthan to the foregoing examples, and all changes which come within themeaning and range of equivalency of the claims are therefore intended tobe embraced.

What is claimed is:
 1. A compound of Formula X:

or a pharmaceutically acceptable salt thereof wherein; V is selectedfrom —C₁₋₆alkyl, -substituted C₁₋₆alkyl, —C₃₋₁₆ carbocycle, -substitutedC₃₋₁₆ carbocycle, —C₃₋₁₆ heterocycle, -substituted C₃₋₁₆ heterocycle,-aryl, -substituted aryl, -heteroaryl, -substituted heteroaryl, whereinsaid carbocycles, heterocycles, aryls, and heteroaryls defined hereinfor V are further selected from monocyclic, bicyclic, and tricyclicsystems, wherein the bicyclic and tricyclic systems are further selectedfrom fused, non-fused, and spiro systems and wherein said substituentsare further selected from —H, -halo, -hydroxyl, —NO₂, —CN, —C₁₋₆ alkyl,—C₁₋₆ alkoxy, —OQ₁, —CF₃, —COOR₂, —NR₃R₄; —COR, —COOR, —SO₂, —SO₂NR₃R₄,and —C₁₋₆ alkylQ₁, —C₁₋₆ alkyl-CO—C₁₋₆ alkyl Q₁, —C₁₋₆ alkyl-NR₃— C₁₋₆alkyl Q₁, —C₁₋₆ alkyl-SO₂C₁₋₆ alkyl Q₁, —C₁₋₆ alkyl-SO₂NR₃— C₁₋₆ alkylQ₁, —C₁₋₆ alkyl-NR₃SO₂— C₁₋₆ alkyl Q₁, —C₁₋₆ alkyl-NR₃CO— C₁₋₆ alkyl Q₁,—C₁₋ ₆ alkyl-CONR₃— C₁₋₆ alkyl Q₁, —C₂₋₆ alkyl-O— C₁₋₆ alkyl Q₁; Q₁ isselected from C₃₋₁₆ carbocycle, substituted C₃₋₁₆ carbocycle, C₃₋₁₆heterocycle, substituted C₃₋₁₆ heterocycle, aryl, substituted aryl,heteroaryl, substituted heteroaryl wherein said carbocycles,heterocycles, aryls, and heteroaryls are further selected frommonocyclic, bicyclic, and tricyclic systems, wherein the bicyclic andtricyclic systems are further selected from fused, non-fused, and spirosystems and wherein said substituents are further selected from —H,-halo, -hydroxyl, —NO₂, —CN, —C₁₋₆ alkyl, —C₁₋₆ alkoxy, —CF₃, —COOR₂,—NR₃R₄; —COR, —COOR, —SO₂, and —SO₂NR₃R₄; and R₃ and R₄ areindependently selected from —H, —C₁₋₆ alkyl, —C₁₋₆ substituted alkyl,aryl, heteroaryl, substituted aryl, substituted heteroaryl, and —COOR₂;alternatively R₃ and R₄ are taken together with the adjacent N to form acycle selected from:

with the proviso that only one of R₃ or R₄ can be —COOR₂.
 2. Apharmaceutical composition comprising a compound or salt of claim 1 anda pharmaceutically acceptable carrier.
 3. The composition of claim 2further comprising at least one other agent used for treatment of AIDSor HIV infection selected from nucleoside HIV reverse transcriptaseinhibitors, non-nucleoside HIV reverse transcriptase inhibitors, HIVprotease inhibitors, HIV fusion inhibitors, HIV attachment inhibitors,CCR5 inhibitors, CXCR4 inhibitors, HIV budding or maturation inhibitors,and HIV integrase inhibitors, and a pharmaceutically acceptable carrier.4. The composition of claim 3 wherein the other agent is dolutegravir.5. A method for treating HIV infection comprising administering acompound of claim 1, or a pharmaceutically acceptable salt thereof, to apatient in need thereof.
 6. The method of claim 5 further comprisingadministering at least one other agent used for treatment of AIDS or HIVinfection selected from nucleoside HIV reverse transcriptase inhibitors,non-nucleoside HIV reverse transcriptase inhibitors, HIV proteaseinhibitors, HIV fusion inhibitors, HIV attachment inhibitors, CCR5inhibitors, CXCR4 inhibitors, HIV budding or maturation inhibitors, andHIV integrase inhibitors.
 7. The method of claim 6 wherein the otheragent is dolutegravir.
 8. The method of claim 6 wherein the other agentis administered to the patient prior to, simultaneously with, orsubsequently to the compound of claim 1.